Condensed bicyclic RAF inhibitors and their use

Abstract

This invention provides novel RAF inhibitors and methods of use for the treatment of various diseases, including colorectal cancer and melanoma. [Solution] This disclosure generally relates to improvements in the synthesis of condensed bicyclic Raf inhibitors of formula (I), for example, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. This disclosure also relates to methods for using compounds, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, for treating diseases such as cancer, including colorectal cancer. JPEG2026143514000140.jpg46155

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 057,536, filed on 28 July 2020, which disclosure is incorporated herein by reference in whole.

[0002] This disclosure generally relates to novel RAF inhibitors and methods of use thereof for the treatment of various diseases, including colorectal cancer and melanoma, but is not limited to these. [Background technology]

[0003] Mutations resulting in uncontrolled signaling via the RAS-RAF-MAPK pathway are found in more than one-third of all cancers. RAF kinases (A-RAF, B-RAF, and C-RAF) are integral parts of this pathway and are associated with B-RAF mutations commonly seen in clinical practice. While most B-RAF V600E-mutated skin cancers are sensitive to approved B-RAF-selective agents, B-RAF V600E-mutated colorectal cancers are surprisingly unresponsive to these agents as monotherapy due to the function of other RAF family members and require combination therapy. B-RAF-selective therapy has not shown clinical benefit for atypical B-RAF (non-V600E), other RAFs, and RAS-driven tumors.

[0004] U.S. Patent No. 10,183,939 discloses racemic Raf inhibitors that exhibit binding affinity to B-RAF V600E and C-RAF, which are incorporated herein by reference in their entirety. These pan-RAF inhibitors are identified as promising candidates to overcome resistance mechanisms associated with clinically approved B-RAF selective agents. [Overview of the project]

[0005] This disclosure relates to compounds that are Raf inhibitors. In embodiments, the compounds of this disclosure are pan-Raf inhibitors.

[0006] The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: Chemical Diagram (wherein, Ring A is a 5-membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms as ring members, R 1 or R 2 one is selected from substituted C 1-8 alkyl, unsubstituted C 5-8 alkyl, substituted or unsubstituted C 1-8 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted heteroaryl, and the other R 1 or R 2 is H, or alternatively, R 1 and R 2 , together with the atoms to which they are bonded, form a 5- or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and the ring is substituted or unsubstituted, when Ring A is imidazole, substituted aryl is not Chemical Diagram , when Ring A is imidazole, R 1 and R 2 , together with the atoms to which they are bonded, do not form an unsubstituted phenyl ring).

[0007] In an embodiment of the compound of formula (I), Ring A is imidazole, pyrazole, or triazole. In an embodiment, Ring A is Chemical Diagram .

[0008] In this embodiment, R 1 This is a monocyclic or bicyclic substituted or unsubstituted aryl. In the embodiment, the bicyclic aryl is a condensed bicyclic aryl.

[0009] This disclosure also relates to compounds of formula (IA), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: [ka] (In the formula, R 1 or R 2 One of them is substitution or non-substitution C 5-8 Alkyl, substituted, or unsubstituted C 1-8 Selected from haloalkyl, substituted aryl, substituted or unsubstituted heterocyclyl, or substituted heteroaryl, and the other R 1 or R 2 Is it H? Alternatively, R 1 and R 2 They are N, O, or S along with the atoms to which they are bonded. A 5-membered or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms, selected from the above, is formed, and this ring is substituted or unsubstituted. Substituting aryls are, [ka] Instead, R 1 and R 2 They do not form unsubstituted phenyl compounds with the atoms to which they are bonded.

[0010] In embodiments of the compound of formula (I) or (IA), R 1 and R 2 These, together with the atoms to which they are bonded, form a 5-membered or 6-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and this ring is substituted or unsubstituted. In embodiments, R1 and R 2 These, together with the atoms to which they are bonded, form a six-membered partially unsaturated or unsaturated ring containing 0 or 1 nitrogen atom in the ring, and this ring is substituted or unsubstituted. In the embodiment, R 1 and R 2 These, together with the atoms to which they are bonded, form a substituted or unsubstituted phenyl ring or a substituted or unsubstituted pyridyl ring. In the embodiment, R 1 and R 2 These, along with the atoms to which they are bonded, form a substituted or unsubstituted tetrahydropyridyl ring.

[0011] This disclosure also relates to compounds of formula (IB), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: [ka] (In the formula, R 1 or R 2 One of them is selected from substituted aryls, substituted or unsubstituted heterocyclyls, or substituted heteroaryls. Substituting aryls are, [ka] isn't it).

[0012] In embodiments of formula (I), (IA), or (IB), R 1 is a substituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted heteroaryl. In this embodiment, R 1 is a substituted phenyl or a substituted 5-membered or 6-membered N-heteroaryl. In the embodiment, R 1 is a substituted phenyl, substituted pyridyl, substituted pyrazole, substituted pyrimidinyl, or substituted thiophenyl. In this embodiment, R 1is a monocyclic or bicyclic substituted aryl, or a monocyclic or bicyclic substituted heteroaryl. In the embodiment, the bicyclic aryl or bicyclic heteroaryl is a fused bicyclic aryl or fused bicyclic heteroaryl. In the embodiment, R 1 These are substituted indazoles or substituted benzimidazoles.

[0013] In embodiments of formula (I), (IA), or (IB), R 1 is an unsubstituted or substituted heterocycline containing 0, 1, or 2 heteroatoms selected from N, O, or S. In embodiments, R 1 These are substituted or unsubstituted tetrahydropyrans.

[0014] In embodiments of formula (I), (IA), or (IB), R 1 is a substitution or non-substitution C 5-6 It is alkyl.

[0015] In embodiments of formula (I), (IA), or (IB), R 1 It is substituted with one or two substituents.

[0016] In embodiments of formula (I), (IA), or (IB), the substituents are halogens, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl groups, R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, Alkyl alkyl groups, haloalkyl groups, and cycloalkyl groups are independently classified as -OR A -CN, -SOR C , -NR A R B , or -NR D R E It is arbitrarily replaced by 1 to 3 elements selected from the following: R D and R E These, together with the N atom to which they are bonded, form a 5-membered or 6-membered saturated or partially unsaturated ring containing one or two heteroatoms selected from N, O, or S, and this saturated or partially unsaturated ring is C 1-6 It is arbitrarily substituted with alkyl.

[0017] In embodiments of formula (I), (IA), or (IB), the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3 Selected from alkyl)2.

[0018] In embodiments of formula (I), (IA), or (IB), the substituents on the substituted aryl or substituted heteroaryl are methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3selected from alkyl)2.

[0019] In an embodiment of formula (I), (I-A), or (I-B), the compound has (R) or (S) stereochemistry at the carbon indicated by *.

[0020] The present disclosure also relates to a compound selected from Table A-1, Table A-2, or Table A-3, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0021] The present disclosure also relates to a compound of formula (II), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

Chemical Structure

[0022] In an embodiment of formula (II), X1 and X 2 is N. In an embodiment, X 1 and X 2 are both CH.

[0023] In an embodiment of Formula (II), R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In an embodiment, R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted thiophenyl.

[0024] In an embodiment of Formula (II), R 4 is -NHC(O)R 5 , -NHC(O)CH2R 5 , -NHC(O)CH(CH3)R 5 , or -NHR 5 .

[0025] In an embodiment of Formula (II), R 5 is a substituted or unsubstituted group selected from alkyl, 3- to 6-membered carbocyclyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl. In an embodiment, R 5 is a substituted or unsubstituted group selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrazole, or triazole .

[0026] In an embodiment of Formula (II), R F is H or methyl.

[0027] In an embodiment of Formula (II), the substituent is halogen, -OR A , -NR A R B , -SO2R C , -SOR C,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl groups, R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups; alkyl groups, haloalkyl groups, and cycloalkyl groups are independently -OR A -CN, -SOR C , or -NR A R B It is arbitrarily replaced by 1 to 3 elements selected from the following.

[0028] In embodiments of formula (II), the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3 Selected from alkyl)2.

[0029] In the embodiment of formula (II), R 5 It is substituted with one or more substituents selected from halogen, methyl, ethyl, propyl, isopropyl, -CN, -OH, or -NH2.

[0030] In the embodiment of formula (II), the compound has (R) or (S) stereochemistry at the carbon indicated by *.

[0031] The present disclosure also relates to a compound selected from Table B, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0032] The present disclosure also relates to a compound of formula (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

Chemical Structure

[0033] In an embodiment of formula (III), R 6 is -C(O)NHR 5 or -C(O)NHCH2R 5 .

[0034] In an embodiment of formula (III), R 5 is substituted or unsubstituted aryl. In an embodiment, R 5 is substituted or unsubstituted phenyl.

[0035] In an embodiment of formula (III), R 6 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, R 6is a monocyclic or bicyclic substituted aryl, or a monocyclic or bicyclic substituted heteroaryl. In the embodiment, the bicyclic aryl or bicyclic heteroaryl is a fused bicyclic aryl or fused bicyclic heteroaryl. In the embodiment, R 6 These are substituted or unsubstituted indazoles or substituted or unsubstituted benzimidazoles.

[0036] In the embodiment of formula (III), the substituents are halogens, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl groups, R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups; alkyl groups, haloalkyl groups, and cycloalkyl groups are independently -OR A -CN, -SOR C , or -NR A R B It is arbitrarily replaced by 1 to 3 elements selected from the following.

[0037] In embodiments of formula (III), the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3Alkyl), or -CH2N(C 1-3 Selected from alkyl)2.

[0038] In the embodiment of formula (III), R 6 is a substituted aryl, substituted heterocyclyl, or substituted heteroaryl, and the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), -CH2N(C 1-3 Alkyl)2, optionally substituted phenyl, or optionally substituted heteroaryl. In this embodiment, R 6 is a substituted aryl or substituted heteroaryl, and the substituent is one or two C 1-3 It is a phenyl or pyrazole substituted with an alkyl group.

[0039] This disclosure also relates to compounds selected from Table C, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

[0040] This disclosure also relates to compounds selected from Table D, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

[0041] This disclosure relates to a pharmaceutical composition comprising one of the compounds disclosed herein and a pharmaceutically acceptable excipient or carrier.

[0042] In embodiments of the pharmaceutical composition, the composition further comprises an additional therapeutic agent. In embodiments, the additional therapeutic agent is selected from antiproliferative or antitumor agents, cell proliferation inhibitors, anti-invasion agents, growth factor function inhibitors, anti-angiogenic agents, steroids, targeted therapy agents, or immunotherapy agents.

[0043] This disclosure relates to a method for treating a RAF kinase-mediated condition, comprising administering an effective amount of any one of the compounds disclosed herein.

[0044] In embodiments of the treatment method, a condition is treatable by inhibition of one or more Raf kinases. In embodiments, the condition is selected from cancer, sarcoma, melanoma, skin cancer, hematological malignancy, lymphoma, carcinoma, or leukemia. In the embodiment, the condition is selected from Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastases to the central nervous system from tumors originating outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancer; head and neck squamous cell carcinoma; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; metastatic melanoma; or thyroid cancer.

[0045] This disclosure relates to a method for treating cancer, comprising administering an effective amount of any one of the compounds disclosed herein.

[0046] In embodiments of a method for treating cancer, the cancer comprises at least one mutation in BRAF kinase. In embodiments, the cancer comprises BRAF V600E Includes mutations.

[0047] In embodiments, cancer is selected from melanoma, thyroid cancer, Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastoma, astrocytoma, ependymoma, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, hematological cancers, leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, kidney cancer, sarcoma, uveal melanoma, or skin cancer. In embodiments, cancer is BRAF V600EMelanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid cancer, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary cancer, BRAF V600E hairy cell leukemia, BRAF V600E Non-small cell lung cancer, or BRAF V600E It is a pilocytic astrocytoma. In this embodiment, the cancer is colorectal cancer. [Modes for carrying out the invention]

[0048] All publications, patents, and patent applications (including their drawings and appendices) are incorporated by reference in all purposes to the same extent as any individual publication, patent, or patent application, drawing, or appendix is ​​specifically and individually indicated to be incorporated by reference in all purposes.

[0049] definition The following terms are expected to be readily understood by those skilled in the art, but their definitions are provided below to facilitate the explanation of the subject matter currently disclosed.

[0050] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numbers and / or ranges. The term “about” is understood to mean a value close to the listed value. Furthermore, the phrases “less than approximately [value]” or “greater than approximately [value]” should be understood in consideration of the definition of the term “about” provided herein. The terms “about” and “approximately” may be used interchangeably.

[0051] Throughout this specification, numerical ranges are provided for specific quantities. It should be understood that these ranges include all subranges within them. Thus, the range "50-80" includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be endpoints of the ranges it encompasses (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0052] The terms "a" or "an" refer to one or more of the entities; for example, "RAF inhibitor" refers to one or more RAF inhibitors or at least one RAF inhibitor. For this reason, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. Furthermore, a reference to "inhibitor" with the indefinite article "a" or "an" does not preclude the possibility of two or more inhibitors existing, unless the context clearly requires the existence of only one inhibitor.

[0053] As used herein, the verb “including” and its conjugations are used in its non-restrictive sense, meaning that the items following the word are included, but not excluded, except for items not specifically mentioned. The present invention may appropriately “include,” “consist of,” or “essentially consist of” the steps, elements, and / or reagents described in the claims.

[0054] It should be further noted that claims can be drafted to exclude any element. Therefore, this statement is intended to serve as a prerequisite for using exclusive terms such as "only" or "only" in relation to the description of elements in the claims or the use of "negative" limitations.

[0055] The term "pharmaceutically acceptable salt" includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form salts, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonate. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid by any of the many known methods.

[0056] The term “to treat” means to reduce, alleviate, delay, decrease, improve, or manage at least one symptom of the condition in question. The term “to treat” may also mean to prevent, delay the onset (i.e., the period before the clinical appearance of the condition), or reduce the risk of the onset or worsening of the condition.

[0057] The compounds of the present invention, or their pharmaceutically acceptable salts, contain at least one chiral center. Compounds of the present invention having one chiral center yield enantiomers, and their absolute stereochemistry can be expressed as (R)- and (S)-, or (+) and (-). If a compound of the present invention has three or more chiral centers, the compound may exist as a diastereomer or other stereoisomer. This disclosure includes all such possible isomers, whether or not they are specifically described herein, as well as their racemic and optically pure forms. Optically active (+) and (-) or (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or they can be separated using conventional methods, such as chromatography and fractional crystallization. Conventional methods for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or, for example, using chiral high-pressure liquid chromatography (HPLC). This includes the resolution of the racemic mixture (or racemic mixture of the salt or derivative) used. Where a compound described herein contains an olefin double bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0058] A "stereoisomer" refers to a compound that is composed of the same atoms bonded together by the same bonds but has different, incompatible three-dimensional structures. This disclosure intends to describe various stereoisomers and mixtures thereof, which include "enantiomers," which refer to two stereoisomers that are mirror images of each other and cannot be superimposed.

[0059] A "tautomer" refers to a proton shift from one atom in a molecule to another atom in the same molecule. This disclosure includes tautomers of any such compound.

[0060] "Effective dose" means the amount of the formulation according to the present invention sufficient to perform a condition, disorder, or treatment of a condition when administered to a patient. The "effective dose" will vary depending on the active ingredient, the condition, disorder, or condition to be treated and its severity, as well as the age, weight, health status, and responsiveness of the mammal to be treated.

[0061] The term “therapeutically effective” as applied to dosage or quantity refers to the amount of compound or pharmaceutical formulation that, after administration to a patient in need, produces the desired clinical benefit.

[0062] As used herein, “subjects” may include humans, non-human primates, mammals, rats, mice, cattle, horses, pigs, sheep, goats, dogs, cats, etc. Subjects may include, but are not limited to, individuals suspected of having or at risk of having cancer, including colorectal cancer and melanoma.

[0063] "Mammals" include humans, as well as both domesticated animals (e.g., laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domesticated animals (e.g., wild animals, etc.).

[0064] All weight percentages referenced herein (i.e., "weight %", "wt.%", and w / w) are measured relative to the total weight of the pharmaceutical composition unless otherwise indicated.

[0065] As used herein, “substantially” or “substantial” refers to the complete or near-complete range or degree of action, feature, property, state, structure, characteristic, or result. For example, an object enclosed “substantially” would mean that the object is completely enclosed or nearly completely enclosed. The exact acceptable range of deviation from absolute completeness may, in some cases, depend on the specific context. However, generally speaking, as completion approaches, the result will be the same as, as absolute and complete completion would be. The use of “substantially” is equally applicable when used in a negative implication to refer to the complete or near-complete absence of action, feature, property, state, structure, characteristic, or result. For example, a composition “substantially” without another active ingredient will either completely lack the other active ingredient or nearly completely lack it. The other active ingredient is the same as the effect when the other active ingredient is completely lacking. In other words, a composition “substantially” without an ingredient or element or another active ingredient may still contain such a characteristic, as long as its measurable effect is not present.

[0066] The term "halo" refers to halogens. In particular, the term refers to fluorine, chlorine, bromine, and iodine.

[0067] "Alkyl" or "alkyl group" refers to a fully saturated, linear or branched hydrocarbon chain group that is bonded to the rest of the molecule by a single bond. It includes alkyl groups containing any number of carbon atoms, but not limited to 12. Alkyl groups containing up to 12 carbon atoms are C1-C 12 Alkyl atoms, which are alkyl groups containing up to 10 carbon atoms, are C1-C 10 Alkyl groups containing up to six carbon atoms are C1-C6 alkyl groups, and alkyl groups containing up to five carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl groups, C4 alkyl groups, C3 alkyl groups, C2 alkyl groups, and C1 alkyl groups (i.e., methyl groups). C1-C6 alkyl groups include all the parts described above for C1-C5 alkyl groups, but also include C6 alkyl groups. 10 Alkyl includes all the parts described above for C1-C5 alkyl and C1-C6 alkyl, but also C7, C8, C9, and C 10 Alkyl groups are also included. Similarly, C1-C 12 Alkyl includes all of the above parts, but C 11 and C 12 Alkyl compounds are also included. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated herein, alkyl groups may be optionally substituted.

[0068] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused or cross-linked ring systems having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, with the remainder of the molecule bonded by single bonds. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specifically stated herein, cycloalkyl groups may be optionally substituted.

[0069] "Haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halo groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated herein, haloalkyl groups may be optionally substituted.

[0070] "Aryl" refers to a hydrocarbon ring system group comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused or bridging ring systems. Aryl groups include, but are not limited to, aryl groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, the term "aryl" means that optionally substituted aryl groups are included.

[0071] "Heterocyclyl," "heterocycle," or "heterocycle" refers to a stable 3-20 membered ring group consisting of 2-12 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyls or heterocycles include heteroaryls as defined below. Unless otherwise specifically stated herein, heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused or bridging ring systems: the nitrogen, carbon, or sulfur atoms of the heterocyclyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized; the heterocyclyl group can be partially... They can be partially or completely saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specifically stated herein, heterocyclyl groups can be optionally substituted. In the embodiment, the heterocyclyl, heterocycle, or heterocycle is a stable 3-20 membered non-aromatic ring group, which consists of 2-12 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0072] "N-heterocyclyl" refers to a heterocyclyl radical defined as containing at least one nitrogen atom, and the bond site of the heterocyclyl radical to the rest of the molecule is via the nitrogen atom in the heterocyclyl radical. Unless otherwise specifically stated herein, the N-heterocyclyl group may be optionally substituted.

[0073] "Heteroaryl" refers to a 5-20 membered cyclic group comprising a hydrogen atom; 1-13 carbon atoms; 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and at least one aromatic ring. For the purposes of the present invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused or bridging cyclic systems; the nitrogen, carbon, or sulfur atoms of the heteroaryl group may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, in Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, heteroaryl groups may be substituted as desired.

[0074] "N-heteroaryl" refers to a heteroaryl radical as defined above, containing at least one nitrogen atom, where the bonding site of the heteroaryl radical to the remainder of the molecule is via the nitrogen atom in the heteroaryl radical. Unless otherwise specifically stated herein, the N-heteroaryl group may be optionally substituted.

[0075] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyryl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl) in which at least one hydrogen atom is replaced by a non-hydrogen atom (e.g., halogen atom, but not limited to) For example, F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are substituted by a higher-order bond (e.g., a double or triple bond) to a heteroatom (e.g., oxygen in groups such as oxo groups, carbonyl groups, carboxyl groups, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). For example, "substituted" means one or more hydrogen atoms are substituted by a higher-order bond (e.g., a double or triple bond) to a heteroatom (e.g., oxygen in groups such as oxo groups, carbonyl groups, carboxyl groups, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). g R h , -NR g C(=O)R h , -NRg C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NR g R h , -OR g , -SR g -SOR g , -SO2R g , -OSO2R g , -SO2OR g ,=NSO2R g , and -SO2NR g R h It includes any of the above groups that are substituted with -C(=O)R. "Substituted" also means that one or more hydrogen atoms are -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g -CH2SO2NR g R h This means any of the above groups that are substituted by R. g and R hThese are the same or different, independently of any of the above groups, which are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are substituted by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. By addition, each of the above-mentioned groups may be optionally substituted with one or more of the above-mentioned groups.

[0076] Compound of the present invention This disclosure relates to a pan-RAF inhibitor having the structure of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: [ka] (In the formula, ring A is a five-membered heterocyclic ring or heteroaryl ring containing one, two, or three nitrogen atoms as ring members.) R 1 or R 2 One of them is substitution C 1-8 Alkyl, unsubstituted C 5-8 Alkyl, substituted, or unsubstituted C 1-8 Selected from haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted heteroaryl, and the other R 1 or R 2 Is it H? Alternatively, R1 and R 2 These atoms, together with the atoms to which they are bonded, form a 5-membered or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and this ring is substituted or unsubstituted. If ring A is an imidazole, then a substituted aryl (e.g., R) 1 or R 2 )teeth, [ka] Instead, If ring A is an imidazole, then R 1 and R 2 (These atoms, along with the atoms to which they are bonded, do not form an unsubstituted phenyl ring.)

[0077] In the embodiment of formula (I), ring A is imidazole, pyrazole, or triazole. [ka] That is the case.

[0078] In embodiments, this disclosure relates to compounds of formula (IA), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: [ka] (In the formula, R 1 or R 2 One of them is substitution or non-substitution C 5-8 Alkyl, substituted, or unsubstituted C 1-8 Selected from haloalkyl, substituted aryl, substituted or unsubstituted heterocyclyl, or substituted heteroaryl, and the other R 1 or R 2 Is it H? Alternatively, R 1 and R 2These atoms, together with the atoms to which they are bonded, form a 5-membered or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and this ring is substituted or unsubstituted. Substitution aryl (for example, R 1 or R 2 )teeth, [ka] Instead, R 1 and R 2 They do not form unsubstituted phenyl compounds with the atoms to which they are bonded.

[0079] In embodiments of formula (I) or (IA), the substituents are halogens, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl groups, R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, Alkyl alkyl groups, haloalkyl groups, and cycloalkyl groups are independently classified as -OR A -CN, -SOR C , -NR A R B , or -NR D R E It is arbitrarily replaced by 1 to 3 elements selected from the following: R D and R EThese, together with the N atom to which they are bonded, form a 5-membered or 6-membered saturated or partially unsaturated ring containing one or two heteroatoms selected from N, O, or S, and this saturated or partially unsaturated ring is C 1-6 It is arbitrarily substituted with alkyl.

[0080] In embodiments, this disclosure relates to compounds of formula (IB), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: [ka] (In the formula, R 1 or R 2 One of them is selected from substituted aryls, substituted or unsubstituted heterocyclyls, or substituted heteroaryls. Substituting aryls are, [ka] isn't it).

[0081] In embodiments of formula (I), (IA), or (IB), the substituents are halogens, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl; R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyls; R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups; alkyl groups, haloalkyl groups, and cycloalkyl groups are independently -OR A -CN, -SOR C , or -NRA R B It is arbitrarily replaced by 1 to 3 elements selected from the following.

[0082] In embodiments of formula (I), (IA), or (IB), the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3 Selected from alkyl)2.

[0083] In embodiments of formula (I), (IA), or (IB), the substituent on the substituted aryl or substituted heteroaryl is a halogen, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl; R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyls; R C C 1-6 Alkyl and C 1-6 The substituents are selected from haloalkyl groups. In embodiments, the substituents are methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, and -CH2C H2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3 Selected from alkyl)2.

[0084] In embodiments of formula (I), (IA), or (IB), the substituent on the substituted aryl is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -OR A , -NR A R B -CN, or -C(O)C 1-6 Selected from alkyl groups.

[0085] In embodiments of formula (I) or (IA), R 1 This is a substituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted heteroaryl. In the embodiment, the substituted aryl is a substituted phenyl. In the embodiment, the substituted heteroaryl is a substituted N-heteroaryl. In the embodiment, the substituted heteroaryl is a substituted 5-membered or 6-membered N-heteroaryl.

[0086] In embodiments of formula (I), (IA), or (IB), R 1 R is a substituted phenyl, substituted pyridyl, substituted pyrazole, substituted pyrimidinyl, or substituted thiophenyl. In embodiments of formula (I), (IA), or (IB), R 1 These are substituted phenyl, substituted pyridyl, or substituted pyrazole.

[0087] In embodiments of formula (I), (IA), or (IB), R 1 is a substituted or unsubstituted heterocyclyl containing 0, 1, or 2 heteroatoms selected from N, O, or S. In embodiments, R 1 is a substituted or unsubstituted tetrahydropyran. In the embodiment, R 1 is either a substitution or a non-substitution. [ka] That is the case.

[0088] In the embodiment of formula (IB), R 1 is a substituted or unsubstituted heterocyclyl containing 0, 1, or 2 heteroatoms selected from N, O, or S. In embodiments, R 1 is a substituted or unsubstituted 5-membered or 6-membered heterocycline containing 0, 1, or 2 heteroatoms selected from N, O, or S. In embodiments, R 1 is a substituted or unsubstituted saturated heterocycline containing 0, 1, or 2 heteroatoms selected from N, O, or S. In embodiments, R 1 R is a substituted or unsubstituted saturated 5-membered or 6-membered heterocycline containing 0, 1, or 2 heteroatoms selected from N, O, or S. In embodiments, R 1 These are substituted or unsubstituted tetrahydropyrans.

[0089] In embodiments of formula (I) or (IA), R 1 is a substitution or non-substitution C 5-6 It is alkyl. In this embodiment, C 5-6 Alkyl groups can be linear or branched.

[0090] In embodiments of formula (I), (IA), or (IB), R 1 is a monocyclic substituted aryl or monocyclic substituted heteroaryl. In the embodiment of formula (I), R 1 is a bicyclic substituted or unsubstituted aryl or a bicyclic substituted heteroaryl. In embodiments of formula (I), (IA), or (IB), R 1 This is a bicyclic substituted aryl or bicyclic substituted he It is a terroraryl. In embodiments of formula (I), (IA), or (IB), R 1 is a condensed biringu substituted aryl or condensed biringu substituted heteroaryl. In the embodiment of formula (I), R 1is a substituted or unsubstituted indazole, or a substituted or unsubstituted benzimidazole. In embodiments of formula (I), (IA), or (IB), R 1 These are substituted indazoles or substituted benzimidazoles.

[0091] In embodiments of formula (I) or (IA), R 1 or R 2 is substituted with one, two, or three substituents. In embodiments of formula (I) or (IA), R 1 or R 2 It is substituted with one or two substituents.

[0092] In the embodiment of formula (IB), R 1 is substituted with one, two, or three substituents. In embodiments of formula (IB), R 1 It is substituted with one or two substituents.

[0093] In embodiments of formula (I) or (IA), R 1 and R 2 These, together with the atoms to which they are bonded, form a 5-membered or 6-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and this ring is substituted or unsubstituted. In embodiments, R 1 and R 2 These atoms, along with the atoms to which they are bonded, form a six-membered partially unsaturated or unsaturated ring containing zero or one nitrogen atom within the ring, and this ring is substituted or unsubstituted.

[0094] In the embodiment of formula (IA), R 1 and R 2 These, together with the atoms to which they are bonded, form a phenyl ring, which can be substituted or unsubstituted. In the embodiment, R 1 and R 2 Together with the atoms to which they are bonded, they form a phenyl ring, thereby forming a benzimidazole ring having an imidazole ring represented by formula (IA), which is substituted or unsubstituted.

[0095] In the embodiment of formula (IA), R 1 and R 2 These, together with the atoms to which they are bonded, form a pyridyl ring, which can be substituted or unsubstituted. In the embodiment, R 1 and R 2 Together with the atoms to which they are bonded, they form a pyridyl ring, thereby forming an imidazopyridine ring having an imidazole ring represented by formula (IA), which may be substituted or unsubstituted.

[0096] In the embodiment of formula (IA), R 1 and R 2 These, together with the atoms to which they are bonded, form a tetrahydropyridyl ring, which is substituted or unsubstituted. In the embodiment, R 1 and R 2 Together with the atoms to which they are bonded, they form a tetrahydropyridyl ring, thereby forming a tetrahydroimidazopyridine ring having an imidazole ring represented by formula (IA), which may be substituted or unsubstituted.

[0097] In embodiments of formula (I) or (IA), R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a 5-membered or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and the ring is unsubstituted.

[0098] In embodiments of formula (I) or (IA), R 1 and R 2 These, together with the atoms to which they are bonded, form a 5-membered or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the ring is substituted with 1, 2, 3, or 4 substituents. In embodiments, the ring is substituted with 1 or 2 substituents.

[0099] In the embodiment, any of the configurations described in the embodiment of formula (I), (IA), or (IB) may be used. The substitution may be applicable to embodiments of formula (II) or (III).

[0100] In embodiments of formula (I), (IA), or (IB), the compound is a racemic mixture. In embodiments, the compound is a (R) stereoisomer. In embodiments, the compound is a (S) stereoisomer.

[0101] In the embodiment, the compound of formula (I), (IA), or (IB) is selected from Table A-1, A-2, or A-3, or from its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0102] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0103] [Table 2-1] [Table 2-2]

[0104] [Table 3]

[0105] In embodiments, this disclosure relates to a compound of formula (II), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. [ka] (In the formula, X 1 and X 2 These are N or CH, respectively. R 1 is substitution C 1-8 Alkyl, unsubstituted C 5-8 Alkyl, substituted, or unsubstituted C 1-8 Selected from haloalkyls, substituted or unsubstituted aryls, substituted or unsubstituted heterocyclines, or substituted or unsubstituted heteroaryls, R 4 -NR F C(O)R 5 , -NR F C(O)CH2R 5 , -NR F C(O)CH(CH3)R 5 , or -NR F R 5 And, R 5 is a substituent or non-substituent selected from carbocyclyl, aryl, heterocyclyl, or heteroaryl, R F is H or C 1-3 (Selected from alkyl groups).

[0106] In embodiments of the compound of formula (II), X 1 and X 2 One of them is N. In this embodiment, X 1 N and X 2 CH is. In the embodiment, X 2 N and X 1 CH is. In the embodiment, X 1 and X 2 Both are CH.

[0107] In embodiments of the compound of formula (II), R 1is a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted heteroaryl. In this embodiment, R 1 is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyrimidinyl, or a substituted or unsubstituted thiophenyl. In the embodiment, R 1 R is a substituted or unsubstituted phenyl. In this embodiment, R 1 It is a substituted phenyl compound.

[0108] In embodiments of the compound of formula (II), R 4 is -NHC(O)R 5 -NHC(O)CH2R 5 ,-NHC(O)CH(CH3)R 5 , or -NHR 5 In this embodiment, R 4 is -NHC(O)R 5 -NHC(O)CH2R 5 , or -NHR 5 That is the case.

[0109] In embodiments of the compound of formula (II), R 5 R is a substituent or non-substituent selected from alkyl, 3-6 membered carbocyryl, phenyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl. In embodiments, R 5 R is a substituent or non-substituent selected from 3-6 membered carbocyclyl, phenyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl. In embodiments, R 5 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In the embodiment, R 5 is a substituted or unsubstituted heterocyclyl containing one or two heteroatoms selected from N, O, or S. In embodiments, R 5 is a substituted or unsubstituted 5-membered or 6-membered heterocycline containing one or two heteroatoms selected from N, O, or S. In embodiments, R 5is a substituted or unsubstituted saturated heterocycline containing one or two heteroatoms selected from N, O, or S. In embodiments, R 5 is a substituted or unsubstituted saturated 5-membered or 6-membered heterocycline containing one or two heteroatoms selected from N, O, or S. In embodiments, R 5 R is a substituted or unsubstituted azetidine, pyrrolidine, piperidine, piperazine, or morpholine moiety. In embodiments, R 5 is a substituent or non-substituted selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, azetidine, pyrrolidine, piperidine, piperazine, or morpholine, pyridine, thiazole, imidazole, pyrazole, or triazole.

[0110] In embodiments of the compound of formula (II), R 5 is a substituted or unsubstituted 5-6 member heteroaryl. In the embodiment, R 5 This is a substituted or unsubstituted 5-6 member heteroaryl compound containing at least one nitrogen atom as a ring member. In the embodiment, R 5 These are substituted or unsubstituted pyridines, thiazoles, imidazoles, pyrazoles, or triazoles.

[0111] In embodiments of the compound of formula (II), R F is H or methyl. In the embodiment, R F H is H.

[0112] In the embodiment of formula (II), the substituents are halogens, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or -C(O)C 1-6 Selected from alkyl; R A and R BThese are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyls; R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups; alkyl groups, haloalkyl groups, and cycloalkyl groups are independently -OR A -CN, -SOR C , or -NR A R B It is arbitrarily replaced by 1 to 3 elements selected from the following.

[0113] In embodiments of formula (II), the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3 Selected from alkyl)2.

[0114] In the embodiment of formula (II), R 5 These are methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), or -CH2N(C 1-3 It is substituted with substituents selected from alkyl)2. In the embodiment, R 5 It is substituted with one or more substituents selected from halogen, methyl, ethyl, propyl, isopropyl, -CN, -OH, or -NH2.

[0115] In the embodiment of formula (II), R 1 is substituted with one, two, or three substituents. In the embodiment of formula (II), R 1 is substituted with one or two substituents. In the embodiment of formula (II), R 1 This is a non-substitution.

[0116] In the embodiment of formula (II), R 5 is substituted with one, two, or three substituents. In the embodiment of formula (II), R 5 is substituted with one or two substituents. In the embodiment of formula (II), R 5 This is a non-substitution.

[0117] In the embodiments, any substituent described in the embodiment of formula (II) may be applicable to the embodiments of formula (I), (IA), (IB), or (III).

[0118] In the embodiment of formula (II), the compound is a racemic mixture. In the embodiment, the compound is a (R) stereoisomer. In the embodiment, the compound is a (S) stereoisomer.

[0119] In the embodiment, the compound of formula (II) is selected from Table B, or from its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0120] [Table 4-1] [Table 4-2]

[0121] In embodiments, this disclosure relates to a compound of formula (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. [ka] (In the formula, R 6 is -C(O)NR F R 5 -C(O)NR F CH2R 5 , substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, R 5 is a substituent or non-substituent selected from carbocyclyl, aryl, heterocyclyl, or heteroaryl, R F is H or C 1-3 (Selected from alkyl groups).

[0122] In embodiments of the compound of formula (III), R 6 is -C(O)NR F R 5 or -C(O)NR F CH2R 5 In this embodiment, R 6 is -C(O)NHR 5 or -C(O)NHCH2R 5 That is the case.

[0123] In embodiments of the compound of formula (III), R 5 is a substituted or unsubstituted aryl. In this embodiment, R 5 These are substituted or unsubstituted phenyl compounds.

[0124] In embodiments of the compound of formula (III), R 6 is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In the embodiment, a monocyclic substituted aryl or monocyclic substituted heteroaryl. In the embodiment, R 6 is a bicyclic substituted aryl or monocyclic substituted heteroaryl. In the embodiment, R 6 is a condensed bicyclic substituted aryl or condensed bicyclic substituted heteroaryl. In the embodiment, R 6 These are substituted or unsubstituted indazoles, or substituted or unsubstituted benzimidazoles.

[0125] In embodiments of the compound of formula (III), R 6 The substituents are substituted aryl or substituted heteroaryl, and the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), -CH2N(C 1-3 Alkyl)2, optionally substituted phenyl, optionally substituted heteroaryl. In embodiments of the compound of formula (III), R 6 R is a substituted aryl or substituted heteroaryl, and the substituent is selected from optionally substituted phenyl or optionally substituted 5-membered or 6-membered heteroaryls. In the embodiment, R 6 is a substituted aryl or substituted heteroaryl, where the substituent is selected from phenyl or optionally substituted 5-membered or 6-membered N-heteroaryls. In embodiments, R 6 is a substituted aryl or substituted heteroaryl, where the substituent is selected from phenyl or optionally a substituted 5-membered N-heteroaryl. In the embodiment, R 6 is a substituted aryl or substituted heteroaryl, and the substituent is one or two C 1-3 Selected from alkyl-substituted phenyl or pyrazole.

[0126] In the embodiment of formula (III), the substituents are halogens, -OR A , -NR A R B , -SO 2R C -SOR C ,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -C(O)C 1-6Alkyl, aryl, or heteroaryl; R A and R B These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyls; R C C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups; alkyl groups, haloalkyl groups, cycloalkyl groups, aryl groups, and heteroaryl groups are independently C 1-6 Alkyl, -OR A -CN, -SOR C , or -NR A R B It is arbitrarily replaced by 1 to 3 elements selected from the following.

[0127] In embodiments of formula (II), the substituents are halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(O)CH3, -CN, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-CH2NH2,-CH2NH(C 1-3 Alkyl), -CH2N(C 1-3 Selected from alkyl(2), optionally substituted phenyl, and optionally substituted heteroaryl.

[0128] In the embodiment of formula (III), R 5 is substituted with one, two, or three substituents. In the embodiment of formula (III), R 5 is substituted with one or two substituents. In the embodiment of formula (III), R 5 This is a non-substitution.

[0129] In the embodiments, any substituent described in the embodiment of formula (III) may be applicable to the embodiments of formula (I), (IA), (IB), or (II).

[0130] In the embodiment, the compound of formula (III) is selected from Table C, or from its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0131] [Table 5]

[0132] In embodiments, this disclosure relates to the compounds of Table D, or their pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0133] [Table 6]

[0134] In embodiments, the compounds disclosed herein have a pERK A375 (1 hour) pIC in the range of about 4 to about 9 (including any value and partial ranges between them). 50 In embodiments, the compounds disclosed herein have pERK A375 (1 hour) pIC in the range of about 5 to about 8 (including any value and partial ranges between them). 50 In embodiments, the compounds of the disclosed herein have values ​​of approximately 5.0, approximately 5.1, approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, approximately 6.5, approximately 6.6, approximately 6.7, approximately 6.8, approximately 6.9, approximately 7.0, approximately 7.1, approximately 7.2, approximately 7.3, approximately 7.4, approximately 7.5, approximately 7.6, approximately 7.7, approximately 7.8, approximately 7.9, or approximately 8.0 (including any value in between) of pERK A375 (1 hour) pIC 50 It has a value.

[0135] In embodiments, the compounds disclosed herein are pERK HCT116 dimers (1 hour) pIC in the range of about 4 to about 9 (including any value and partial ranges between them). 50 In embodiments, the compounds disclosed herein have pERK HCT116 dimer (1 hour) pIC in the range of about 5 to about 8 (including any value and partial ranges between them). 50In embodiments, the compounds of the present disclosure have pERK HCT116 dimers (1 hour) pIC at approximately 5.0, approximately 5.1, approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, approximately 6.5, approximately 6.6, approximately 6.7, approximately 6.8, approximately 6.9, approximately 7.0, approximately 7.1, approximately 7.2, approximately 7.3, approximately 7.4, approximately 7.5, approximately 7.6, approximately 7.7, approximately 7.8, approximately 7.9, or approximately 8.0 (including any value in between). 50 It holds.

[0136] In embodiments, the compounds of the present disclosure have a pERK A375 monomer / pERK HCT116 dimer ratio in the range of about 0.01 to about 2.5 (including any value and partial ranges between therein). In embodiments, the compounds of the present disclosure have a pERK A375 monomer / pERK HCT116 dimer ratio in the range of about 0.03 to about 2.0 (including any value and partial ranges between therein). In embodiments, the compounds of the present disclosure have a pERK monomer / dimer ratio of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 (including any value between therein). In embodiments, the compounds of the present disclosure have a pERK A375 monomer / pERK HCT116 dimer ratio of 2 or less. The pERK A375 monomer / pERK HCT116 dimer ratio is calculated using potency in nM units.

[0137] In embodiments, the compounds disclosed herein have a pERK HCT116 (2 hours) absolute pIC in the range of about 6 to about 9 (including any value and partial ranges between them). 50 In embodiments, the compounds of the present disclosure have p in the range of about 6.5 to about 8 (including any value and partial ranges between them). ERK HCT116 (2 hours) Absolutely PIC 50In embodiments, the compounds of the present disclosure have a pERK HCT116 (2 hours) absolute pIC of about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0 (including any value in between). 50 It has. In embodiments, the compound of the present disclosure has a pERK of about 6.5 or more, HCT116 (2 hours) absolute pIC 50 It holds.

[0138] In embodiments, the compounds disclosed herein have a pERK WiDr (2 hours) absolute pIC in the range of about 6 to about 9 (including any value and partial ranges between them). 50 In embodiments, the compounds disclosed herein have a pERK WiDr (2 hours) absolute pIC in the range of about 6.5 to about 8 (including any value and partial ranges between them). 50 In embodiments, the compounds of the present disclosure have pERK WiDr (2 hours) absolute pIC of about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0 (including any value in between). 50 In embodiments, the compounds disclosed herein have a pERK WiDr (2 hours) absolute pIC of about 6.5 or higher. 50 It holds.

[0139] In embodiments, the compounds of the present disclosure have pGI50 3D HCT116 in the range of about 6 to about 9 (including any value and partial ranges in between). In embodiments, the compounds of the present disclosure have pGI50 3D HCT116 in the range of about 6.5 to about 8 (including any value and partial ranges in between). In embodiments, the compounds of the present disclosure have pGI50 3D HCT116 of about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0 (including any value in between). In embodiments, the compounds of the present disclosure have pGI50 3D HCT116 of about 6.5 or higher.

[0140] In embodiments, the compounds of the Disclosure have a pGI50 3D WiDr in the range of about 6 to about 9 (including any value and partial ranges in between). In embodiments, the compounds of the Disclosure have a pGI50 3D WiDr in the range of about 6.5 to about 8 (including any value and partial ranges in between). In embodiments, the compounds of the Disclosure have a pGI50 3D WiDr of about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0 (including any value in between). In embodiments, the compounds of the Disclosure have a pGI50 3D WiDr of about 6.5 or higher.

[0141] In embodiments, the compounds of the disclosed herein have a human liver microsome (HLM) intrinsic clearance (CLint) in the range of about 1 μL / min / mg to about 25 μL / min / mg (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have an HLM CLint in the range of about 1 μL / min / mg to about 20 μL / min / mg (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have an HLM CLint in the range of about 1 μL / min / mg to about 15 μL / min / mg (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have an HLM CLint in the range of about 1 μL / min / mg to about 10 μL / min / mg (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have an HLM CLint of approximately 1 μL / min / mg, approximately 2 μL / min / mg, approximately 3 μL / min / mg, approximately 4 μL / min / mg, approximately 5 μL / min / mg, approximately 6 μL / min / mg, approximately 7 μL / min / mg, approximately 8 μL / min / mg, approximately 9 μL / min / mg, approximately 10 μL / min / mg, approximately 11 μL / min / mg, approximately 12 μL / min / mg, approximately 13 μL / min / mg, approximately 14 μL / min / mg, or approximately 15 μL / min / mg (including any value in between). In embodiments, the compounds of the disclosed herein have an HLM CLint of less than approximately 15 μL / min / mg. In embodiments, the compounds of the disclosed herein have an HLM CLint of less than approximately 20 μL / min / mg. .

[0142] In embodiments, the compounds of the disclosed herein have a mouse liver microsome (MLM) intrinsic clearance (CLint) in the range of approximately 1 μL / min / mg to approximately 130 μL / min / mg (including any value and partial ranges within that range). In embodiments, the compounds of the disclosed herein have an MLM CLint in the range of approximately 1 μL / min / mg to approximately 50 μL / min / mg (including any value and partial ranges within that range). In embodiments, the compounds of the disclosed herein have an MLM CLint in the range of approximately 1 μL / min / mg to approximately 30 μL / min / mg (including any value and partial ranges within that range). In embodiments, the compounds of the disclosed herein have an MLM CLint in the range of approximately 1 μL / min / mg to approximately 20 μL / min / mg (including any value and partial ranges within that range). In embodiments, the compounds of the disclosed herein have an MLM CLint of approximately 1 μL / min / mg, approximately 2 μL / min / mg, approximately 3 μL / min / mg, approximately 4 μL / min / mg, approximately 5 μL / min / mg, approximately 6 μL / min / mg, approximately 7 μL / min / mg, approximately 8 μL / min / mg, approximately 9 μL / min / mg, approximately 10 μL / min / mg, approximately 11 μL / min / mg, approximately 12 μL / min / mg, approximately 13 μL / min / mg, approximately 14 μL / min / mg, approximately 15 μL / min / mg, approximately 16 μL / min / mg, approximately 17 μL / min / mg, approximately 18 μL / min / mg, approximately 19 μL / min / mg, or approximately 20 μL / min / mg (including any value in between). In embodiments, the compounds of the disclosed herein have an MLM CLint of less than approximately 30 μL / min / mg. In embodiments, the compounds of the disclosed herein have an MLM CLint of less than approximately 25 μL / min / mg. In embodiments, the compounds of the disclosed herein have an MLM CLint of less than approximately 20 μL / min / mg.

[0143] In embodiments, the compounds of the Disclosure have a human plasma protein-bound (hPPB) percent free value in the range of about 0.01% to about 15% (including any value and partial ranges therein). In embodiments, the compounds of the Disclosure have an hPPB percent free value in the range of about 0.05% to about 10% (including any value and partial ranges therein). In embodiments, the compounds of the Disclosure have an hPPB percent free value in the range of about 0.1% to about 8% (including any value and partial ranges therein). In embodiments, the compounds of the Disclosure have an hPPB percent free value in the range of about 0.1% to about 5% (including any value and partial ranges therein).

[0144] In embodiments, the compounds of the Disclosure have a mouse plasma protein-bound (mPPB) percent free value in the range of about 0.01% to about 15% (including any value and partial ranges therein). In embodiments, the compounds of the Disclosure have an mPPB percent free value in the range of about 0.05% to about 10% (including any value and partial ranges therein). In embodiments, the compounds of the Disclosure have an mPPB percent free value in the range of about 0.1% to about 8% (including any value and partial ranges therein). In embodiments, the compounds of the Disclosure have an mPPB percent free value in the range of about 0.1% to about 5% (including any value and partial ranges therein).

[0145] In embodiments, the compounds of the disclosed herein have a FESSIF solubility in the range of about 10 mg / L to about 1000 mg / L (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have a FESSIF solubility in the range of about 20 mg / L to about 750 mg / L (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have a FESSIF solubility in the range of about 25 mg / L to about 600 mg / L (including any value and partial ranges therein). In embodiments, the compounds of the disclosed herein have a FESSIF solubility of about 10 mg / L or more. In embodiments, the compounds of the disclosed herein have a FESSIF solubility of about 20 mg / L or more. In embodiments, the compounds of the disclosed herein have a FESSIF solubility of about 25 mg / L or more. In embodiments, the compounds of the disclosed herein have a FESSIF solubility of about 30 mg / L or more.

[0146] therapeutic use This disclosure also relates to formulas (I), (IA), (I-) for treating various diseases and conditions. The present invention relates to methods for using compounds of formula (B), (II), or (III), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In embodiments, compounds of formula (I), (IA), (IB), (II), or (III), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, are useful for treating diseases or conditions involving the abnormal activity of one or more Raf kinases. In embodiments, compounds of formula (I), (IA), (IB), (II), or (III), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, are useful for treating diseases or conditions treatable by inhibition of one or more Raf kinases. RAF kinase inhibition is associated with treating a variety of diseases related to abnormal activity of the MAPK pathway. In embodiments, the condition is treatable by inhibition of RAF kinases such as B-RAF or C-RAF.

[0147] This disclosure also relates to methods for using the compounds in Tables A1-A3 and B-D, or their pharmaceutically acceptable salts, tautomers, or stereoisomers, for treating a variety of diseases and conditions. In embodiments, the compounds in Tables A1-A3 and B-D, or their pharmaceutically acceptable salts, tautomers, or stereoisomers, are useful for treating diseases or conditions involving the abnormal activity of one or more Raf kinases. In embodiments, the compounds in Tables A1-A3 and B-D, or their pharmaceutically acceptable salts, tautomers, or stereoisomers, are useful for treating diseases or conditions treatable by inhibition of one or more Raf kinases. RAF kinase inhibition is associated with treating a variety of diseases related to abnormal activity of the MAPK pathway. In embodiments, the condition is treatable by inhibition of RAF kinases such as B-RAF or C-RAF.

[0148] In embodiments, the disease or condition is cancer. In embodiments, the disease or condition is selected from Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastases to the central nervous system from tumors originating outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancer; head and neck squamous cell carcinoma; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; metastatic melanoma; or thyroid cancer.

[0149] In the embodiments, the disease or condition is melanoma, non-small cell carcinoma, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer, or bile duct cancer. In the embodiments, the disease or condition is colorectal cancer. In the embodiments, the disease or condition is melanoma.

[0150] In the embodiment, the disease or condition is BRAF V600E It is a cancer that includes mutations. In embodiments, the disease or condition is BRAF V600EIt is regulated by BRAF. In the embodiment, the disease or condition is BRAF V600E Melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid cancer, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary cancer, BRAF V600E hairy cell leukemia, BRAF V600E Non-small cell lung cancer, or BRAF V600E It is a pilocytic astrocytoma.

[0151] In this embodiment, the disease or condition is cardiac-facial-cutaneous syndrome and polycystic kidney disease.

[0152] Pharmaceutical composition This disclosure also relates to pharmaceutical compositions comprising compounds of formula (I), (IA), (IB), (II), or (III), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, and pharmaceutically acceptable carriers or excipients. This disclosure also relates to the compounds of Tables A1-A3 and B-D, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. This relates to a pharmaceutical composition comprising a substance and a pharmaceutically acceptable carrier or excipient.

[0153] In some embodiments, the pharmaceutical composition may further contain additional pharmaceutically active agents. These additional pharmaceutically active agents may be antitumor agents.

[0154] In embodiments, additional pharmaceutically active agents are antiproliferative / antineoplastic agents. In embodiments, antiproliferative / antineoplastic agents include alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and nitrosourea); antimetabolites (e.g., gemcitabine and folic acid antimetabolites, e.g., fluoropyrimidines, e.g., 5-fluorouracil and tegafur, larcitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); and antibiotics (e.g., anthracyclines, e.g., adriamycin, bleomycin, doxorubicin, daunomycin). , epirubicin, idarubicin, mitomycin-C, dactinomycin, and mitramycin); antimitotic agents (e.g., vinca alkaloids, e.g., vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids, e.g., TAXOL® (paclitaxel), and taxoteres and polokinase inhibitors); proteasome inhibitors, e.g., carfilzomib and bortezomib; interferon therapy; or topoisomerase inhibitors (e.g., epipodophyllotoxins, e.g., etoposide and teniposide, amsacrin, topotecan, mitoxantrone, and camptothecin).

[0155] In embodiments, additional pharmaceutically active agents are cell proliferation inhibitors. In embodiments, cell proliferation inhibitors are anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, doroxifene, and iodoxifene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), or 5α-reductase inhibitors, such as finasteride.

[0156] In the embodiment, the additional pharmaceutically active agent is an anti-infiltration agent. In the embodiment, the anti-infiltration agent is dasatinib and bosutinib (SKI-606), a metalloproteinase inhibitor, or a urokinase plasminogen activator receptor function inhibitor, or an antibody against heparanase.

[0157] In embodiments, additional pharmaceutically active agents are growth factor function inhibitors. In embodiments, growth factor function inhibitors include growth factor antibodies and growth factor receptor antibodies, e.g., anti-erbB2 antibody trastuzumab [Herceptin®], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., gefitinib, erlotinib, and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazoline-4-amine (CI1033), erbB2 tyrosine kinase inhibitors, e.g. For example, lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, e.g., imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / RAF signaling inhibitors, e.g., farnesyltransferase inhibitors, e.g., sorafenib, tipifarnib, and ronafarnib); inhibitors of cell signaling via MEK and / or AKT kinases, c -kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; aurora kinase inhibitors or cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors.

[0158] In embodiments, the additional pharmaceutically active agent is an anti-angiogenic agent. In embodiments, the anti-angiogenic agent inhibits the effects of vascular endothelial growth factors, such as the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin®); thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib, batalanib, sunitinib, axitinib, and pazopanib.

[0159] In the embodiments, the additional pharmaceutically active agent is a cytotoxic agent. In the embodiments, the cytotoxic agent is fludarivine (Fuldara), cladribine, or pentostatin (Nipent®).

[0160] In this embodiment, the additional pharmaceutically active agent is a steroid. In the embodiment, the steroid is a corticosteroid containing glucocorticoids and mineralocorticoids, for example, acrometasone, acrometasone dipropionate, aldosterone, amcinonide, beclometasone, beclometasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valveate, budesonide, clobetazone, clobetazone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortibazole, deoxycorton, desonide, deoxymetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluchloron, flumetasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, f These include luorocortisone, fluorocortolone, flucortolone caproate, flucortolone pivarate, fluorometholone, flupredniden, flupredniden acetate, flulandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone butepraate, hydrocortisone valveate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone parametasone, mometasone florate monohydrate, prednicarbart, prednisolone, prednisone, thixocortol, thixocortol pivarate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used; for example, a combination of two or more steroids as described herein may be used.

[0161] In this embodiment, the additional pharmaceutically active agent is a targeted therapy agent. In this embodiment, the targeted therapy agent is a PI3Kd inhibitor, such as idelalisib and perifosine.

[0162] In embodiments, additional pharmaceutically active agents are immunotherapeutic agents. In embodiments, immunotherapeutic agents include antibody therapies such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; interferons such as interferon-α; interleukins such as IL-2 (aldesleukin); interleukin inhibitors such as IRAK4 inhibitors; cancer vaccines (including prophylactic and therapeutic vaccines), such as HPV vaccines such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); Toll-like receptor modulators such as TLR-7 or TLR-9 agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0163] In embodiments, the pharmaceutical composition may be used in combination with another therapy. In embodiments, the other therapy is gene therapy, which includes, for example, an approach to replace an abnormal gene such as an abnormal p53 or an abnormal BRCA1 or BRCA2.

[0164] In embodiments, other therapies include immunotherapeutic approaches, such as antibody therapies (e.g., alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab); interferons, such as interferon α; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines (including prophylactic and therapeutic vaccines), such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); Toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0165] The compounds of the present invention may exist in single-crystalline form, as a mixture of crystalline forms, or in amorphous form. Therefore, for pharmaceutical purposes, the compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporative drying. For this purpose, microwave or high-frequency drying may be used.

[0166] In the compounds of the present invention described above, the dosage administered will of course vary depending on the compound used, the mode of administration, the desired treatment, and the disorder being treated. For example, when the compounds of the present invention are administered orally, the daily dose of the compounds of the present invention may range from 0.01 micrograms (μg / kg) to 100 milligrams (mg / kg) per kilogram of body weight.

[0167] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used on their own, but generally, they will be administered in the form of pharmaceutical compositions in which the compounds of the present invention or pharmaceutically acceptable salts thereof are associated with pharmaceutically acceptable adjuvants, diluents, or carriers. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, MEAulton, Churchill Livingstone, 1988.

[0168] Depending on the method of administration of the compound of the present invention, the pharmaceutical composition used to administer the compound of the present invention will preferably contain 0.05 to 99% w (weight percent) of the compound of the present invention, more preferably 0.05 to 80% w of the compound of the present invention, even more preferably 0.10 to 70% w of the compound of the present invention, and even more preferably 0.10 to 50% w of the compound of the present invention (all weight percents are based on the whole composition).

[0169] Pharmaceutical compositions may be administered topically (e.g., on the skin) in the form of, for example, creams, gels, lotions, solvents, or suspensions; systemically by oral administration in the form of, for example, tablets, capsules, syrups, powders, or granules; parenterally by sterile solutions, suspensions, or emulsions for infusion (including intravenous, subcutaneous, intramuscular, intravascular, or infusion); rectally by suppositories; or by inhalation in the form of aerosols.

[0170] When administered orally, the compounds of the present invention are used with an adjuvant or carrier, such as lactose, saccharose, sorbitol, or mannitol; or with starch, such as potato starch. The mixture may be a combination of corn starch or amylopectin; a cellulose derivative; a binder, such as gelatin or polyvinylpyrrolidone; and / or a lubricant, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, or paraffin, and then compressed into tablets. If coated tablets are required, the core prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0171] For the preparation of soft gelatin capsules, the compounds of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using any of the tablet excipients described above. Liquid or semi-solid formulations of the compounds of the present invention may also be filled into hard gelatin capsules. Liquid formulations for oral administration may be in the form of a syrup or suspension, for example, a solution containing the compounds of the present invention, with the remainder being a mixture of sugar, as well as ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain carboxymethylcellulose as a coloring agent, flavoring agent, sweetener (e.g., saccharin), preservative, and / or thickener, or other excipients known to those skilled in the art.

[0172] For intravenous (parenteral) administration, the compounds of the present invention may be administered as a sterile aqueous solution or an oily solution.

[0173] Pharmaceutical compositions can be prepared as liposomes and encapsulated therapeutic agents. For various methods of preparing liposomes and encapsulating therapeutic agents, see, for example, U.S. Patents 3,932,657, 4,311,712, 4,743,449, 4,452,747, 4,830,858, 4,921,757, and 5,013,556. Known methods include the reverse-phase evaporation method described in U.S. Patent 4,235,871. U.S. Patent 4,744,989 also covers the use and preparation methods of liposomes to improve the efficiency or delivery of therapeutic compounds, drugs, and other agents.

[0174] The compounds of the present invention can be passively or actively loaded into liposomes. Active drug loading is typically carried out using a pH (ion) gradient or using encapsulated metal ions. For example, pH gradient loading can be carried out by the methods described in U.S. Patents No. 5,616,341, 5,736,155, 5,785,987, and 5,939,096. Liposome loading using metal ions can be carried out by the methods described in U.S. Patents No. 7,238,367 and 7,744,921.

[0175] The inclusion of cholesterol in liposome membranes has been shown to reduce drug release and / or enhance stability after intravenous administration (see, for example, U.S. Patents 4,756,910, 5,077,056, and 5,225,212). The inclusion of low-cholesterol liposome membranes with continued charged lipids has been shown to provide low-temperature stability and increase circulation after intravenous administration (see U.S. Patent 8,518,437).

[0176] Pharmaceutical compositions may contain nanoparticles. The formation of nanoparticles has been achieved in various ways. Nanoparticles can be produced by precipitating molecules in a water-miscible solvent, then drying and grinding the precipitate to form nanoparticles (U.S. Patent No. 4,726,955). Similar techniques for preparing nanoparticles for pharmaceutical formulations include wet grinding or milling. Other methods involve altering the local charge of the solvent and mixing a low concentration of polymer dissolved in a water-miscible solution with an aqueous phase to form a precipitate by conventional mixing methods (U.S. Patent No. 5,766,635). Other methods include the use of colloidal protectants or surface protectants. This involves mixing an aqueous phase containing a surfactant to reduce the force with a copolymer in an organic solution. Other methods for incorporating additional therapeutic agents into nanoparticles for drug delivery require that the nanoparticles be treated with liposomes or surfactants before drug administration (U.S. Patent No. 6,117,454). Nanoparticles can also be prepared by flash nanoprecipitation (U.S. Patent No. 8,137,699).

[0177] U.S. Patent No. 7,850,990 covers methods for screening combinations of active ingredients and encapsulating those combinations in a delivery vehicle, such as liposomes or nanoparticles.

[0178] The size of the therapeutic dose of the compound of the present invention will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0179] The dosage level, frequency of administration, and duration of treatment of the compounds of the present invention are expected to vary depending on the formulation, clinical indication, patient age, and comorbidities. The standard duration of treatment with the compounds of the present invention is expected to vary from 1 to 7 days for most clinical indications. In cases of recurrent infection or infections associated with tissues or graft materials with insufficient blood supply, including bone / joint, airway, endocardium, and dental tissue, it may be necessary to extend the treatment period beyond 7 days. [Examples]

[0180] This disclosure is generally described herein and will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating specific aspects and embodiments of the invention and are not intended to limit the invention.

[0181] As used herein, the following terms have the given meanings: “Boc” refers to tert-butyloxycarbonyl; “Cbz” refers to carboxybenzyl; “dba” refers to dibenzylideneacetone; “DCM” refers to dichloromethane; “DIPEA” refers to N,N-diisopropylethylamine; “DMA” refers to dimethylacetamide; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “dppf” refers to 1,1'-bis(diphenylphosphino)ferrocene; “” refers to ethyl acetate; “EtOH” refers to ethanol; “Et2O” refers to diethyl ether; “IPA” refers to isopropyl alcohol; “LiHMD” "S" refers to lithium bis(trimethylsilyl)amide; "mCPBA" refers to meta-chloroperoxybenzoic acid; "MeCN" refers to acetonitrile; "MeOH" refers to methanol; "min" represents minutes; "NMR" refers to nuclear magnetic resonance; "PhMe" refers to toluene; "pTsOH" refers to p-toluenesulfonic acid; "py" refers to pyridine; "rt" refers to room temperature; "SCX" refers to strong cation exchange; "T3P" refers to propylphosphonic anhydride; "Tf2O" refers to trifluoromethanesulfonic anhydride; "THF" refers to tetrahydrofuran; "THP" refers to 2-tetrahydropyranyl; "(UP)LC-MS" refers to (ultra-high performance) liquid chromatography / mass spectrometry. Unless otherwise specified, solvents, reagents, and starting materials were purchased from commercial vendors and used as received. Unless otherwise specified, all reactions were carried out at room temperature. Compound identity and purity were confirmed by LC-MS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nM, and MS was performed in positive and negative electrospray mode (m / z: 150~800). 2 μL aliquots were sequentially injected into a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm) and maintained at 40°C. According to the gradient below, A (0.1% (v / v) in water) The sample was eluted at a flow rate of 0.6 mL / min using a mobile phase system consisting of (formic acid) and B (0.1% (v / v) formic acid in MeCN). Retention time RT is reported in minutes. [Table 7]

[0182] NMR was also used to characterize the final compounds. NMR spectra were obtained using a Bruker AVIII 400 Nanobay equipped with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds on silica thin-layer chromatography (TLC) plates were measured.

[0183] The compounds were purified by flash column chromatography on silica or by preparative LC-MS. LC-MS purification was performed using a Waters 3100 mass detector in positive and negative electrospray mode (m / z: 150-800) with a Waters 2489 UV / Vis detector. Samples were eluted at a flow rate of 20 mL / min on an Xbridge™ preparative C18 5 μM OBD 19 × 100 mm column using a mobile phase system consisting of A (0.1% (v / v) formic acid aqueous solution in water) and B (0.1% (v / v) formic acid in MeCN) according to the gradient below. [Table 8]

[0184] The chemical names used herein were generated using mol2nam (structure-to-name conversion by OpenEye Scientific Software). Starting materials were purchased from commercial sources or synthesized according to literature procedures.

[0185] Synthesis of common intermediates Example 1. Synthesis of 5-fluoro-3,4-dihydro-1H-1,8-naphthyridine-2-one [ka] Step 1: tert-butyl N-(4-fluoro-2-pyridyl)carbamate 2-amino-4-fluoropyridine (400 g, 3.57 mol) was placed in a 10 L stationary reactor and then dissolved in DCM (4 L) under a nitrogen atmosphere. DMAP (43.6 g, 357 mmol) was added, and the reaction mixture was cooled to 10°C. Boc2O (934 g, 4.2 mol) was added as a solution in DCM (1 L) over 1.5 hours. The reaction mixture was stirred at room temperature for 2 hours. Next, the reaction mixture was treated with N,N-dimethylethylenediamine (390 mL, 3.57 mmol) and heated to 40°C overnight. The reaction mixture was cooled to room temperature, diluted with DCM (2 L), and washed with water. The aqueous layer was extracted with another 2 L of DCM, the organic matter was washed with water and brine, and the mixture was dried over MgSO4. The solid pulverized during evaporation of the solvent, was filtered, and washed with petroleum ether to obtain tert-butyl N-(4-fluoro-2-pyridylcarbamate (505 g, 2.38 mol, 67% yield) as a cream-colored solid product. ULC-MS (ES+, low acidity): 1.64 min, m / z 213.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 10.13 (1H, d, J = 1.7Hz), 8.26 (1H, dd, J = 9.4Hz, 5.7 Hz), 7.60 (1H, dd, J = 12.3Hz, 2.4Hz), 6.94 (1H, ddd, J = 8.2Hz, 5.7Hz, 2.4Hz), 1.47 (9H, s).

[0186] Step 2: tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate 126 g, 593.7 mmol of tert-butyl N-(4-fluoro-2-pyridyl) carbamate and 223 mL, 1.48 mol of N,N,N,N-tetramethylethylenediamine were dissolved in 1.7 L of dry THF, and the mixture was then cooled to -78°C under a nitrogen atmosphere. To this solution, n-BuLi (2.5 M in hexane, 285 mL, 712.5 mmol) was added, and the mixture was stirred for a further 10 minutes. Next, sec-BuLi (1.2 M in cyclohexane, 509 mL, 712.5 mmol) was added, and the reaction temperature was kept below -70°C while stirring for 1 hour. After this time, 226 g, 890.6 mmol of iodine in 300 mL of THF was added dropwise over 30 minutes, while the temperature was kept below -65°C. The reaction mixture was stirred at -70°C for another 10 minutes, then saturated NH4Cl (400 mL) aqueous solution was added, then The reaction was quenched by adding a solution of sodium thiosulfate (134.1 g, 848.2 mmol) dissolved in water (600 mL), and the temperature was raised to -25°C. The reaction mixture was warmed to room temperature, transferred to a 5 L separator, extracted with siRNA (2 × 1.5 L), and then washed with brine (500 mL). The organic phase was dried with MgSO4, and the solvent was removed by vacuum. The residue was dissolved in DCM (500 mL), passed through a 2 kg silica pad, washed with DCM (10 × 1 L), and then the product was eluted from the column using siRNA / petroleum ether with a gradient of 10-100% (1 L for every 10% increase) as the eluent to obtain tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (154.6 g, 457.1 mmol, yield 77%) as a white solid. UPLC-MS (ES+, low acidity): 1.60 min, m / z 339.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 9.47 (1H, s), 8.33 (1H, dd, J = 8.7Hz, 5.5Hz), 7.19 (1H, dd, J = 7.3Hz, 5.5Hz), 1.46 (9H, s).

[0187] Step 3: 5-Fluoro-3,4-dihydro-1H-1,8-naphthyridine-2-one 263.3 g, 778.72 mmol of tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate, 120 mL, 1.01 mol of 3,3-dimethoxypropa-1-ene, and 285 mL, 1.64 mol of DIPEA were dissolved in 2.2 L of DMF and 440 mL of water, and the mixture was degassed under a nitrogen atmosphere for 20 minutes. Palladium(II) acetate (17.5 g, 77.9 mmol) was added to this mixture, and the reaction mixture was degassed for 15 minutes. The mixture was then heated at 110 °C for 18 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The solvent was removed under reduced pressure, the residue was dissolved in water, and the pH was acidified to approximately 1-2 with a 2N HCl solution. The pH was then basicized to approximately 9 with a solid NaHCO3 solution, followed by extraction with DCM (2 × 2 L). The organic phases were combined, washed with water and brine, and dried over MgSO4. siRNA (2 L) was added to the solution, and the organic matter was passed through a silica plug and eluted with 40% siRNA in DCM. The fractions containing the product were combined, the solvent was removed under vacuum, and a solid was obtained. This solid was slurryed with cold Et2O (300 mL) and filtered. The solid was washed with Et2O, then with petroleum ether, and dried to obtain 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (5.7 mg, 343.1 mmol, yield 44%) as a pale yellow solid. UPLC-MS (ES+, low acidity): 1.04 min. m / z 167.0 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 10.69 (1H, s), 8.29-7.90 (1H, m), 6. 92 (1H, dd, J = 8.8Hz, 5.7Hz, 1H), 2.88 (2H, dd, J = 8.3Hz, 7.1Hz), 2.57-2.47 (2H, m).

[0188] Example 2. Synthesis of 6-hydroxychroman-3-carboxylic acid [ka] Step 1: 2-Hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde 2,5-Dihydroxybenzaldehyde (400g, 2.90mol) and pyridinium To a solution of 36.4 g, 144.8 mmol of p-toluenesulfonate in 7.5 L of DCM, 3,4-dihydro-2H-pyran (396.3 mL, 4.34 mol) was added dropwise over 10 minutes, and the reaction mixture was stirred overnight at 30°C. The reaction mixture was washed with water (1.5 L), the organic layer was separated and passed through a 1.5 kg silica pad, which was then washed with DCM (2.5 L), 25% ethyl acetate in petroleum ether (2.5 L), and finally 50% ethyl acetate in petroleum ether (2.5 L). The fractions containing the product were combined, and the solvent was removed by vacuum. The residue was gradually diluted with petroleum ether (1.75 L) and cooled to 10°C to obtain a high-viscosity slurry. The product was filtered, washed with petroleum ether (2 × 150 mL), and dried to obtain 2-hydroxy-5-tetrahydropyran-2-yloxybenzaldehyde (570.7 g, 2.57 mol, yield 89%) as a yellow solid. UPLC-MS (E S+, low acidity): 1.64 min, m / z 223.0 [M+H]+.1H NMR ( 400 MHz, DMSO-d6) δ / ppm: 10.35 (1H, s), 10. 23 (1H, s), 7.32-7.19 (2H, m), 6.94 (1H, d, J = 8.9Hz), 5.36 (1H, t, J = 3.3Hz), 3.77 (1H, ddd, J = 11.2Hz, 8.8Hz, 3.6Hz), 3.59-3.49 (1H, m), 1.94-1.45 (6H, m).

[0189] Step 2: tert-butyl6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate 107 g, 481.5 mmol of 2-hydroxy-5-tetrahydropyran-2-yloxybenzaldehyde was dissolved in 750 mL of diglym, and 133 g, 962.9 mmol of K2CO3 was added. The reaction mixture was then heated to 140°C, and 155 mL, 1059.2 mmol of tert-butyl acrylate in 75 mL of DMF was added over 10 minutes at approximately 110°C; the reaction mixture was then stirred at 140°C for a further 5 hours. The reaction mixture was cooled to room temperature overnight, filtered, and the solvent was removed by vacuum. The reaction mixture was suspended in 2.5 L of butyl and 2.5 L of water, and the phases were separated. The aqueous phase was extracted with 2.5 L of butyl, and the combined organic layers were washed with 50% brine, and the solvent was removed by vacuum. The crude product was dissolved in DCM, loaded onto a 2 kg silica pad, and flushed with siRNA / petroleum ether at a 10-25% gradient to obtain tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (122.5 g, 368.5 mmol, 77% yield) as a yellow solid. UPLC-MS (ES+, low acidity): 2.18 min, m / z nd. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 7.38 (1H, s), 7.05 (1H, d, J = 2.9 Hz), 6.9 4 (1H, dd, J = 8.8, 2.9 Hz), 6.79 (1H, dd, J = 8.8, 0.7 Hz), 5.35 (1H, t, J = 3.3 Hz), 4.82 (2H, d, J = 1.4 Hz), 3.78 (1H, ddd, J = 11.8, 8.6, 3.6 Hz), 3.58-3.49 (1H, m), 1.92-1.66 (3H, m), 1.66-1.52 (3H, m), 1.49 (s, 9H).

[0190] Step 3: tert-butyl 6-hydroxy-2H-chromen-3-carboxylate 110.4 g, 332.1 mmol of tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate was suspended in 1.2 L of MeOH at room temperature, and pyridinium p-toluenesulfonate (8.35 g, 33.2 mmol) was added. The reaction mixture was heated to 34°C for 3 hours. The solvent was removed by vacuum, the crude product was dissolved in 1 L of ELISA, and washed with 750 mL of water. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to obtain a yellow solid. This solid was suspended in petroleum ether, and the solvent was removed by vacuum to obtain 82 g, 330.3 mmol, 99% yield of tert-butyl 6-hydroxy-2H-chromene-3-carboxylate as a yellow solid. UPLC-MS (ES-, low acidity): 1.71 min, m / z 247.2 [MH]-. 1H N MR (400 MHz, DMSO-d6) δ / ppm: 9.17 (1H, s), 7 .33 (1H, s), 6.76-6.64 (3H, m), 4.77 (2H, d, J = 1.4Hz), 1.49 (9H, s).

[0191] Step 4 tert-butyl 6-hydroxychroman-3-carboxylate 177.3 g, 714.1 mmol of tert-butyl 6-hydroxy-2H-chromen-3-carboxylate was suspended in 2.5 L of MeOH at room temperature, and 10 wt.% palladium (on carbon powder) and 50% wet (15.2 g, 142.8 mmol) were added. An H2 balloon was attached to the reaction chamber, excess H2 was added, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 5 hours. The crude product was filtered through Celite, washed with MeOH, and the filtrate was concentrated under vacuum to obtain 171 g, 683.2 mmol, 96% yield of tert-butyl 6-hydroxychromen-3-carboxylate as a pale cream solid. UPLC-MS (ES+, low acidity): 1.64 min, m / z nd. 1H NMR (400 MHz, DMSO-d6) δ / ppm: 8.81 (1H, s), 6.60-6.52 (1H, m), 6.47 (2H, d, J = 7.7Hz), 4. 19 (1H, dd, J = 10.6Hz, 3.0Hz), 3.96 (1H, dd , J = 10.6Hz, 7.4Hz), 2.96-2.73 (3H, m), 1.40 (9H, s).

[0192] Step 5: 6-Hydroxychroman-3-carboxylic acid 23 g, 91.9 mmol of tert-butyl 6-hydroxychroman-3-carboxylate was dissolved in 250 mL of DCM, and 48.3 mL, 630.35 mmol of TFA was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed by vacuum, and the mixture was azeotropically mixed with toluene (100 mL). The residue was slurryed with Et2O and filtered to obtain 6-hydroxychroman-3-carboxylic acid (16.8 g, 86.5 mmol, 94% yield) as a pale pink solid. UPLC-MS (ES+, low acidity): 1.08 min, m / z 194.1 [M+ H]+. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 12.60 (1H, s), 8.81 (1H, s), 6.60-6.53 (1H, m), 6.52-6.45 (2H, m), 4.22 (1H, dd, J = 10.7Hz, 3 .0Hz), 4.06-3.96 (1H, m), 2.97-2.77 (3H, m).

[0193] Example 3. Synthesis of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid [ka] 6-Hydroxychroman-3-carboxylic acid (45.3 g, 233.3 mmol) and 5-fluoro-3,4-dihydro-1H-1,8-naphthyridine-2-one (38.8 g, 233.3 mmol) were suspended in DMSO (230 mL), and K2CO3 (119.7 g, 865.8 mmol) was added separately. The reaction mixture was heated at 98 °C for 48 hours. Next, it was cooled to 60 °C, diluted with water (2 L), and extracted with ELISA (750 mL). The aqueous layer was separated and gradually added to a solution of citric acid (179.3 g, 933.2 mmol) in water (400 mL) to obtain a cream-colored solid, which was filtered and mixed with water / acetone (1:1) and Et Washed with 2O and dried, 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (74.7 g, 219.5 mmol, yield 94%) was obtained as a cream-colored solid. UPLC-MS (ES+, low acidity) degree): 1.26 min, m / z 341.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 12.69 (1H, s), 10.46 (1H, s), 7.95 (1H, d, J = 5.8Hz), 6.97 (1H, d, J = 2.8Hz), 6.89 (1H, dd, J = 8.8Hz, 2.8Hz), 6.84 (1H, t, J = 8.8Hz), 6.24 (1H, d, J = 5.8Hz) , 4.33 (1H, dd, J = 10.9Hz, 3.1Hz), 4.20-4.10 (1H, m), 3.06-2.95 (3H, m), 2.92 (2H, t, J = 8.4Hz, 7.0Hz), 2.59-2.51 (2H, m).

[0194] Example 4. Synthesis of 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol and 5-[3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one [ka] Step 1: Methyl 6-hydroxy-2H-chromen-3-carboxylate 6-hydroxy-2H-chromene-3-carboxylic acid (16 g, 83.3 mmol) in MeOH (200 mL) was mixed with sulfuric acid (0.44 mL, 8.33 mmol), and the reaction was heated to 70°C until complete. The solvent was removed by vacuum, the residue was dissolved in DCM, and washed with water. The organic layer was separated, passed through a 100 g silica pad, and eluted with DCM (500 mL), and then with 50% siRNA (2 × 500 mL) in petroleum ether. The resulting solid was slurryed in petroleum ether, filtered, and dried to obtain methyl 6-hydroxy-2H-chromene-3-carboxylate (14.1 g, 68.4 mmol, yield 82%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.38 min, m / z 207.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ / ppm : 9.19 (1H, s), 7.46 (1H, d, J = 1.4Hz), 6.79-6.65 (2H, m), 6.70 (1H, s), 4.82 (2H, d, J = 1.4Hz), 3.75 (3H, s).

[0195] Step 2: Methyl 6-hydroxychroman-3-carboxylate Methyl 6-hydroxy-2H-chromen-3-carboxylate (53.3 g, 258.3 mmol) was suspended in MeOH (600 mL) at room temperature, and palladium (10 wt.%) on carbon powder, 50% wet (2.75 g, 25.8 mmol) was added under a nitrogen atmosphere. An H2 balloon was attached to the reaction chamber, excess H2 was added, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 3 hours. The crude product was filtered through Celite, washed with MeOH, and the solvent was removed under vacuum to obtain methyl 6-hydroxychromen-3-carboxylate (50.1 g, 233.9 mmol, 91% yield) as a cream-colored solid. UPLC-MS (ES+, low acidity): 1.27 min, m / z 209.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 8.83 (1H, s), 6.56 (1H, dd, J = 8.1, 1.0 Hz), 6.48 (2H, dd , J = 9.7Hz, 1.8Hz), 4.22 (1H, dd, J = 10.8H z, 3.2Hz), 4.04 (1H, dd, J = 10.7Hz, 7.6 Hz) , 3.64 (3H, s), 3.10-2.98 (1H, m), 2.89 (2H, d, J = 6.9 Hz).

[0196] Step 3: Methyl 6-benzyloxychroman-3-carboxylate Benzyl bromide (2.85 mL, 23.97 mmol) was gradually added under a nitrogen atmosphere at room temperature to a stirred mixture of methyl 6-hydroxychroman-3-carboxylate (4.16 g, 19.98 mmol), K2CO3 (8.28 g, 59.93 mmol), and DMF (100 mL). The reaction mixture was heated to 50 °C and stirred for 1.5 hours, then cooled to room temperature and the solvent was removed by vacuum. The residue was partitioned between water (300 mL) and DCM (300 mL). The organic layers were separated, and the aqueous layer was extracted with DCM (300 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed by vacuum. Column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-50% purified the residue to obtain methyl 6-benzyloxychroman-3-carboxylate (5.9 g, 19.78 mmol, 99% yield) as a colorless oil, which solidified into a white solid upon standing. UPLC-MS (ES+, low acidity): 1.92 min, m / z 299.2 [M+H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 7.46-7.32 (5H, m), 6.79-6.77 (2H, m), 6.73 (1H, d, J = 7.2Hz) , 5.02 (2H, s), 4.44-4.39 (1H, m), 4,14-4.0 8 (1H, m), 3.75 (3H, s), 3.14-2.97 (3H, m).

[0197] Step 4: 6-Benzyloxychroman-3-carboxylic acid Methyl 6-benzyloxychroman-3-carboxylate (5.9 g, 19.78 mmol) was stirred at room temperature for 18 hours in an aqueous solution of NaOH (100 mL, 100 mmol) and THF (100 mL). The organic solvent was removed by vacuum, the resulting mixture was stirred, cooled on ice, and subsequently acidified to approximately pH 5 using concentrated hydrochloric acid. The resulting solid was filtered and dried to obtain 6-benzyloxychroman-3-carboxylic acid (5.1 g, 17.94 mmol, 91% yield) as a white solid. UPLC-MS (ES-, low acidity): 1.71 min, m / z 283.2 [MH]-.1 H NMR (400MHz, CDCl3) δ / ppm: 12.64 (1H, br s), 7.46-7.37 (4H, m), 7.35-7.30 (1H, m), 6.80 (1H, d, J = 2.8Hz), 6.74 (1H, dd, J = 9.2Hz, 2.8Hz), 6.67 (1H, d , J = 9.2Hz), 5.02 (2H, s), 4.27-4.22 (1H, m ), 4.09-4.04 (1H, m), 2.99-2.91 (3H, m).

[0198] Step 5: 6-Benzyloxychroman-3-yl)methanol Dimethyl sulfideborane (13.45 mL, 26.91 mmol) was added at 0°C under a nitrogen atmosphere to a stirred solution of 6-benzyloxychroman-3-carboxylic acid (5.1 g, 17.94 mmol) and THF (200 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C and carefully quenched with water (500 mL). This was extracted with siRNA (2 × 500 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0–10% as the eluent to obtain (6-benzyloxychroman-3-yl)methanol (4.5 g, 16.65 mmol, yield 93%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.69 min, m / z 271.2 [M+H]+. 1 H NM R (400MHz, CDCl3) δ / ppm: 7.46-7.31 (5H, m), 6.78-6.75 (2H, m), 6.72-6.69 (1H, m), 5.01 (2H, s), 4.27 (1H, ddd, J = 10.8Hz, 2.8Hz, 1 .2Hz), 3.99 (1H, dd, J = 10.8Hz, 2.8Hz), 3.77-3.65 (2H, m), 2.92-2.85 (1H, m), 2.59 (1H , dd, J = 16.8Hz, 7.6Hz), 2.33-2.23 (1H, m). No exchangeable protons are observed.

[0199] Step 6: 6-Benzyloxychroman-3-carbaldehyde A 200 mL solution of DMSO (1.77 mL, 24.97 mmol) in DCM was stirred at -78°C under a nitrogen atmosphere. Next, 2.11 mL of oxalyl chloride (24.97 mmol) was added and the mixture was stirred for 20 minutes; a 50 mL solution of (6-benzyloxychroman-3-yl)methanol in DCM was added dropwise while maintaining the temperature below -70°C. Upon completion of the addition, the reaction mixture was stirred for 30 minutes, and triethylamine (5.8 mL, 41.62 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 20 minutes, and then warmed to room temperature. The reaction mixture was diluted with water (200 mL), the organic layer was separated and passed through a phase separator, and the solvent was removed by vacuum. The residue was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-50%, yielding 6-benzyloxychroman-3-carbaldehyde (4.4 g, 16.4 mmol, 99% yield) as a yellow oil. UPLC-MS (ES+, low acidity): 1.82 min, m / z 268.2 [M]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 9.86 (1H, s), 7. 47-7.32 (5H, m), 6.81-6.74 (3H, m), 5.02 (2 H, s), 4.42-4.32 (2H, m), 3.17-3.09 (1H, m) , 3.04-2.93 (2H, m).

[0200] Step 7: 2-(6-benzyloxychroman-3-yl)-1H-imidazole Ammonium hydroxide (25 mL, 750 mmol) was added at room temperature to a stirred solution of 6-benzyloxychroman-3-carbaldehyde (3.9 g, 14.54 mmol), glyoxal (9.96 mL, 87.21 mmol), and MeOH (25 mL). After 1 hour, the reaction mixture was diluted with water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic layer was dried over Na₂SO₄, filtered, and the solvent was removed under vacuum to obtain 2-(6-benzyloxychroman-3-yl)-1H-imidazole (2.4 g, 7.83 mmol, yield 54%) as a yellow solid. UPLC-MS (ES+, low acidity), 1.28 min, m / z 307.3 [M+H]+. 1 1H NMR (400MHz, DMSO-d 6) δ / ppm: 7.46-7.30 (6H, m), 7.08 (1H, d, J = 9.2Hz), 6.83-6.80 (1H, d), 6.79-6.75 (1H, d), 6.71 (1H, d, J = 8.8Hz), 5.03 (2H, s), 4 .40-4.35 (1H, m), 3.97 (1H, t, J = 10.0Hz), 3.31-3.26 (1H, m), 3.15-3.10 (1H, m), 3.05- 2.97 (1H, m). No exchangeable protons are observed.

[0201] Step 8: 2-[[2-(6-benzyloxychroman-3-yl)imidazole-1-yl]methoxy]ethyl-trimethyl-silane Sodium hydride (60% dispersed in mineral oil - 895.6 mg, 22.39 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 2-(6-benzyloxychroman-3-yl)-1H-imidazole (3.43 g, 11.2 mmol) in DMF (5 mL). After 20 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (2.97 mL, 16.79 mmol) was added. The reaction mixture was stirred for 1 hour, then quenched with water (1 mL), and the solvent was removed by vacuum. The residue was partitioned between water (20 mL) and DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-5% as the eluent to obtain 2-[[2-(6-benzyloxychroman-3-yl)imidazole-1-yl]methoxy]ethyl-trimethyl-silane (4.3 g, 9.85 mmol, yield 88%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.67 min, m / z 437.7 [M+H]+. 1 1H NMR (400MHz, CDCl3) δ / ppm: 7.45-7.29 (5H, m), 7.03-7.01 (1H, m), 6.99-6.97 (1H, m), 6.80-6.78 (2H, m), 6.73-6.71 (1H, m), 5.31-5.28 (2H, m), 5.01 (2H, s), 4.44-4.38 (1H, m), 4.12 (1H, t, J = 10.4Hz), 3.55-3.50 (2H, m), 3 .48-3.33 (2H, m), 2.99-2.92 (1H, m), 0.96-0.87 (2H, m), 0.00 (9H, s).

[0202] Step 9 3-[1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol Palladium (10 wt.%) on carbon powder, dry (400 mgl) was added at room temperature to a stirred solution of 2-[[2-(6-benzyloxychroman-3-yl)imidazole-1-yl]methoxy]ethyl-trimethyl-silane (4.3 g, 9.85 mmol) in MeOH (50 mL). An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 2 hours. The crude product was filtered through Celite, washed with MeOH, and the filtrate was concentrated under vacuum to obtain 3-[1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (3.32 g, 9.58 mmol, yield 97%) as a yellow solid. The compound was used directly in the next step without further purification. UPLC-MS (ES+, low acidity): 1.36 min, m / z 347.7 [M +H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 6.98 (1 H, d, J = 1.6Hz), 6.99 (1H, d, J = 1.6Hz), 6. 69 (1H, d, J = 8.8Hz), 6.63 (1H, dd, J = 8.8H z, 3.2Hz), 6.56 (1H, d, J = 3.2Hz), 5.32 (1H , d, J = 10.8Hz), 5.28 (1H, d, J = 10.8Hz), 4 .33 (1H, ddd, J = 10.8Hz, 3.2Hz, 2.4Hz), 4.10 (1H, t, J = 10.4Hz), 3.55-3.50 (3H, m), 3. 33-3.24 (1H, m), 2.94-2.87 (1H, m), 0.91-0.95 (2H, m), 0.10 (9H, s). No exchangeable protons were observed.

[0203] Step 10 [3-[1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]acetate Acetyl chloride (0.94 mL, 13.29 mmol) is mixed with 2-(1-benzylimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-ol (3.07 g, 8.86 mmol), Et3N (1.85 mL, 13.29 mmol), and DCM. The mixture was added to 100 mL of a stirred solution under a nitrogen atmosphere at room temperature. The reaction mixture was stirred for 30 minutes, after which 100 mL of water was added. The mixture was extracted with DCM (2 × 100 mL). The combined organic extract was dried over Na₂SO₄, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-100% as the eluent to obtain [3-[1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]acetate (2.93 g, 7.53 mmol, yield 85%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.48 min. m / z 389.5 [M+H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 7.07-6.99 (2H, m), 6.88-6.81 (3H, m), 5.33-5.27 (2H, m), 4.46-4.41 (1H, m), 4.25-4.18 (1H, m), 3.57-3.50 (2H, m), 3.48-3.38 (2H, m), 3.03-2.95 (1H, m), 2.25 (3H, s), 0.96-0.89 (2H, m), 0.00 (9H, s).

[0204] Step 11 [3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]acetate N-bromosuccinimide (0.46 g, 2.57 mmol) was added to a stirred solution of [3-[1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]acetate (1 g, 2.57 mmol) and DCM (100 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred for 30 minutes and then diluted with water (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-50% as the eluent to obtain [3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]acetate (684 mg, 1.46 mmol, yield 57%) as a yellow oil. UPLC-MS (ES+, low acidity): 2.07 min. m / z 467.2, 469.2 [M+H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 6.98 (1H, s), 6.85-6.80 (3H, m) , 5.33 (2H, s), 4.46-4.41 (1H, m), 4.15-4.0 7 (2H, m), 3.62-3.56 (1H, m), 3.51-3.41 (1H , m), 3.38-3.30 (1H, m), 3.00-2.94 (1H, m), 2.27 (3H, s), 0.96-0.89 (2H, m), 0.00 (9H, s).

[0205] Step 12 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol [3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]acetate (800 mg, 1.71 mmol) was stirred at room temperature in a mixture of 1 M NaOH aqueous solution (10 mL, 10 mmol) and THF (10 mL). After 30 minutes, the reaction was adjusted to approximately pH 5 using 1 M HCl aqueous solution, then diluted with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and the solvent was removed by vacuum to obtain 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (728 mg, 1.71 mmol, yield 100%) as a yellow oil. The compound was used in the next step without further purification. UPLC-MS (ES+, short acidi): 1.87 min, m / z 425.1, 427.1 [M+H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 6.99 (1H, s), 6. 75-6.73 (1H, m), 6.64-6.60 (1H, m), 6.58-6.56 (1H, m), 5.34 (2H, s), 4.80-4.71 (1H, m), 4.42-4.36 (1H, m), 4.06 (1H, t, J = 10.4Hz) , 3.61-3.57 (2H, m), 3.51-3.40 (1H, m), 3.3 7-3.28 (1H, m), 2.95-2.88 (1H, m), 0.96-0.89 (2H, m), 0.00 (9H, s).

[0206] Step 13 5-[3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (2 g, 4.7 mmol), 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (781.2 mg, 4.7 mmol), K2CO3 (2.6 g, 18.81 mmol), and DMSO (5 mL) were combined and stirred at 110°C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a solution of water (100 mL) and citric acid monohydrate (3.95 g, 18.81 mmol). The resulting mixture was extracted with DCM (2 × 100 mL), the combined organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-10% as the eluent to obtain 5-[3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizin-2-one (230 mg, 0.40 mmol, yield 9%) as a yellow solid. UPLC-MS (ES+, low acidity), 1.96 min, m / z 571.2, 573.2 [M+H]+.

[0207] Example 5. Synthesis of 6-[(2-chloro-4-pyridyl)oxy]chroman-3-carboxylic acid and 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]chroman-3-carboxylic acid [ka] Step 1: 6-[(2-chloro-4-pyridyl)oxy]chroman-3-carboxylic acid A solution of 6-hydroxychroman-3-carbone hydrochloride (1.4 g, 6.07 mmol), 2-chloro-4-fluoropyridine (550 μL, 6.09 mmol), and K2CO3 (3.36 g, 24.28 mmol) in DMSO (7.6 mL) was heated to 110 °C for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a solution of citric acid (4.67 g, 24.28 mmol) in water (100 mL). The resulting precipitate was filtered, washed with water, and dried to obtain 6-[(2-chloro-4-pyridyl)oxy]chroman-3-carboxylic acid (1.74 g, 5.69 mmol, yield 94%) as a brown solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.55 min, m / z 306.1 [M+H]+. 1 1H NMR (400 MHz, DMSO-d6) δ / ppm: 12.69 (1H, br s), 8.27 (1H, d, J = 5.7Hz), 7.04 (1H, d, J = 2.9Hz), 6.97-6.89 (3H, m), 6.86 (1H, d, J = 8.8Hz), 4.34 (1H, dd, J = 10.9, 3.2Hz), 4.19-4.13 (1H, m), 3.05-2.95 (3H, m).

[0208] Step 2: 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]chroman-3-carboxylic acid 6-[(2-chloro-4-pyridyl)oxy]chroman-3-carboxylic acid (500 mg, 1.64 mmol), cyclopropanecarboxamide (278.4 mg, 3.27 mmol), and Cs2CO3 (1.07 g, 3.27 mmol) were added to a solution of 1,4-dioxane (16 mL) with (+ / -)-BINAP (203.7 mg, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium (0) (149.7 mg, 0.16 mmol) under a nitrogen atmosphere. The mixture was heated at 100 °C for 20 hours. After cooling to room temperature, the mixture was filtered through Celite and washed with methanol. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-20% as the eluent. The fractions containing the product were combined, the solvent was removed by vacuum, and the residue was suspended in DCM and filtered. The precipitate was washed with DCM and dried to obtain 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]chroman-3-carboxylic acid (272.3 mg, 0.77 mmol, yield 47%) as an off-white solid. UPLC-MS (ES+, low acidity): 1.23 min, m / z 355.2 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.69 (1H, br s), 10.81 (1H, s), 8.15 (1H, d, J = 5.7Hz), 7.63 (1H, d, J = 2.4Hz), 6.97 (1H, d, J = 2.7H z), 6.88 (1H, dd, J = 8.8Hz, 2.7Hz), 6.83 (1 H, d, J = 8.8Hz), 6.59 (1H, dd, J = 5.7Hz, 2. 4Hz), 4.34 (1H, dd, J = 10.7Hz, 2.8Hz), 4.14 (1H, dd, J = 10.7Hz, 6.7Hz), 3.04-2.92 (3H, m), 1.97 (1H, quint, J = 6.2Hz), 0.77 (4H, d, J = 6.2Hz).

[0209] Example 6. Synthesis of 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline hydrochloride [ka] Step 1: Acetate; 1,2,3,4-tetrahydroisoquinoline-7-ol Platinum(IV) oxide (Adams catalyst) (500 mg, 2.2 mmol) was added to 7-hydroxyisoquinoline (5 g, 34.45 mmol) in acetic acid (20 mL) at room temperature. An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 18 hours. The crude product was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was stirred in an acetone / petroleum ether mixture (1:2, 15 mL) for 1 hour, the solid was pulverized, filtered, and vacuum-dried to obtain acetic acid; 1,2,3,4-tetrahydroisoquinoline-7-ol (6.53 g, 31.2 mmol, yield 91%) as a pale yellow solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity) ): 0.36 min, m / z 150.2 [M+H]+.

[0210] Step 2: Benzyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate Benzyl chloroformate (2.05 mL, 14.34 mmol) was added to a stirred solution of THF (15 mL), acetate; 1,2,3,4-tetrahydroisoquinoline-7-ol (2.5 g, 11.95 mmol), and NaOH (35.84 mL, 35.84 mmol). The reaction mixture was stirred for 1 hour, then diluted with water (200 mL) and toluene (200 mL). The organic layer was separated, dried over Na₂SO₄, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-100% toluene eluent in petroleum ether to obtain benzyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (3.3 g, 11.65 mmol, yield 97%) as a white solid. UPLC-MS (ES+, low acidity): 1.65 min, m / z 284.2 [M+H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 7.40 -7.29 (5H, m), 6.98 (1H, d, J = 8.4Hz), 6.70 -6.54 (2H, m), 5.18 (2H, s), 4.61-4.56 (2H, m), 3.75-3.66 (2H, m), 2.81-2.73 (2H, m). No exchangeable protons were observed.

[0211] Step 3: Benzyl 7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylate Benzyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (569 mg, 1.45 mmol) was dissolved in DMF (8 mL), followed by the addition of benzyl bromide (0.21 mL, 1.74 mmol) and K2CO3 (600 mg, 4.34 mmol). The reaction mixture was stirred at 50°C for 1.5 hours, then at room temperature overnight. The solvent was removed under reduced pressure. Water was added, followed by extraction with siRNA (2×). The organic layers were combined, washed with brine (2×), dried over Na2SO4, and the solvent was removed under vacuum. The crude product was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-25% as the eluent to obtain benzyl 7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (428 mg, 1.15 mmol, yield 79%) as a colorless oil. UPLC-MS (ES+, low acidity): 2.12 min, m / z 374.2 [M+H]+. 1 H-NMR (400 MHz, CDCl3) δ / ppm : 7.50-7.28 (10H, m), 7.04 (1H, d, J = 8.4Hz ), 6.81 (1H, dd, J = 8.4Hz, 2.4Hz), 6.72 (1H , br d, J = 12.0Hz), 5.18 (2H, s), 5.04 (2H, s), 4.61 (2H, s), 3.71 (2H, br s), 2.78 (2H, br s).

[0212] Step 4: 7-Benzyloxy-1,2,3,4-tetrahydroisoquinoline hydrochloride Benzyl 7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (196 mg, 0.52 mmol) was mixed with HCl (4N in 1,4-dioxane - 6 mL, 24 mmol), and the reaction mixture was heated to 80°C for 72 hours. The solvent was removed under reduced pressure to obtain 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (144.7 mg, 0.52 mmol, 100% yield) as a cream-colored solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.27 min, m / z 240.2 [M+H]+. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 9.18 (1H, br s), 7.52-7 .37 (4H, m), 7.36-7.27 (1H, m), 7.14 (1H, d, J = 8.4Hz), 6.96-6.89 (2H, m), 5.10 (2H, s) , 4.21 (2H, br s), 3.35-3.28 (2H, t, (underwater)), 2.92 (2H, t, J = 6.0Hz).

[0213] Example 7. Synthesis of 3-methyl-5-(trifluoromethyl)benzene-1,2-diamine [ka] 3-Bromo-4,5-diaminobenzotrifluoride (500 mg, 1.96 mmol), K2CO3 (542 mg, 3.92 mmol), and tetrakis(triphenylphosphine)palladium(0) (227 mg, 0.20 mmol) were mixed under N2, followed by the addition of 2,4,6-trimethylboroxine (0.27 mL, 1.96 mmol). The reaction mixture was stirred at 110°C for 72 hours, after which 2,4,6-trimethylboroxine (0.14 mL, 0.98 mmol), K2CO3 (271 mg, 1.96 mmol), and the second portion of tetrakis(triphenylphosphine)palladium(0) (113 mg, 0.10 mmol) were added. The reaction mixture was stirred overnight at 110°C, followed by the addition of water (20 mL), and then extraction with SiO(2×). The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography using MeOH / DCM with a gradient of 0-5% as the eluent to obtain 3-methyl-5-(trifluoromethyl)benzene-1,2-diamine (82 mg, 0.43 mmol, yield 22%) as a brown oil. UPLC-MS (ES+, low acidity) ): 1.37 min, m / z 191.1 [M+H]+. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 6.70-6.67 (1H, m), 6.63-6.59 (1H, m), 4.81 (2H, s), 4.79 (2H, s), 2.07 (3H, s).

[0214] Example 8. Synthesis of 6-(trifluoromethyl)pyridine-3,4-diamine [ka] Step 1: 5-Nitro-2-(trifluoromethyl)pyridine-4-ol To a solution of 2-(trifluoromethyl)pyridine-4-ol (1000 mg, 6.13 mmol) in cold sulfuric acid (2.46 mL, 46.15 mmol) at 0°C, add nitric acid (fuming, 90% (6.12 mL, 144.04 mmol)) dropwise over 15 minutes, then add the reaction mixture 1 The mixture was heated overnight at 20°C. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was neutralized by adding a 32% aqueous NaOH solution and extracted with siRNA (3×) and n-BuOH. The combined organic phase was dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain 5-nitro-2-(trifluoromethyl)pyridine-4-ol (1.27 g, 6.10 mmol, 100% yield) as a yellow solid. The compound was used in the next step without further purification. UPLC-MS (ES-, low acidity): 1.17 min, m / z 207.1 [MH]-. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 9.00 (1H, s), 7.30 (1H, s).

[0215] Step 2: 4-Chloro-5-nitro-2-(trifluoromethyl)pyridine 5-Nitro-2-(trifluoromethyl)pyridine-4-ol (1.28 g, 6.13 mmol), phosphorus pentachloride (1.91 g, 9.19 mmol), and phosphorus oxychloride (0.86 mL, 9.19 mmol) were stirred overnight at 80°C. The mixture was cooled to room temperature, diluted with DCM, and washed with water, saturated Na2CO3 aqueous solution, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The compound was redissolved in DCM, poured into ice water, and then added with 1 M NaOH aqueous solution. The organic phase was washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain 4-chloro-5-nitro-2-(trifluoromethyl)pyridine (804 mg, 3.55 mmol, yield 58%) as a yellow oil. UPLC-MS (ES-, low acidity): 1.68 min, m / z nd. 1 HN MR (400MHz, DMSO-d6) δ / ppm: 9.43 (1H, s), 8 .58 (1H, s).

[0216] Step 3: 5-Nitro-2-(trifluoromethyl)pyridine-4-amine 4-Chloro-5-nitro-2-(trifluoromethyl)pyridine (752 mg, 3.32 mmol) was dissolved with ammonia in MeOH (30.08 mL, 69.19 mmol) and stirred at room temperature for 3 hours. The solvent was removed by vacuum to obtain 5-nitro-2-(trifluoromethyl)pyridine-4-amine (687 mg, 3.32 mmol, 100% yield) as a yellow solid. The product was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.36 min, m / z 208.1 [M+H] +. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 9.07 (1H, s), 7.44 (1H, s).

[0217] Step 4: 6-(trifluoromethyl)pyridine-3,4-diamine 5-Nitro-2-(trifluoromethyl)pyridine-4-amine (734 mg, 3.54 mmol) was dissolved in pharmaceutically acceptable solution (15 mL) and ethanol (25 mL), followed by the addition of palladium (10 wt.% (238 mg) on ​​carbon powder) under a nitrogen atmosphere. An H2 balloon was attached to the reaction chamber, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 72 hours. The second portion of palladium (10 wt.% on carbon powder, dry (238 mg)) was added, and the mixture was stirred overnight. The crude product was filtered through Celite, washed with pharmaceutically acceptable solution, and the solvent was removed under reduced pressure to obtain 6-(trifluoromethyl)pyridine-3,4-diamine (571 mg, 3.22 mmol, 91% yield) as a colorless oil. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 7.69 (1H, s), 6 .83 (1H, s), 5.79 (2H, br s), 5.21 (2H, br s).

[0218] Example 9. Synthesis of 5-[(dimethylamino)methyl]-3-(trifluoromethyl)benzene-1,2-diamine [ka] Step 1: 4-Chloro-3-nitro-5-(trifluoromethyl)benzoic acid To 1.5 g (6.68 mmol) of 4-chloro-3-(trifluoromethyl)benzoic acid, sulfuric acid (5.34 mL, 100.20 mmol) and nitric acid (fuming, 90% (0.85 mL, 20.04 mmol)) were added, and the reaction mixture was heated at 90°C for 1 hour. The crude product was poured into 150 mL of ice-cold water, filtered, and vacuum-dried to obtain 1.66 g (6.15 mmol, 92% yield) of 4-chloro-3-nitro-5-(trifluoromethyl)benzoic acid as a white solid. UPLC-MS (ES-, low acidity): 1.66 min, m / z 268.1 [MH]-. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 14.22 (1H, br s), 8.78 (1H, d, J = 2.0Hz), 8.44 (1H, d, J = 1.6Hz).

[0219] Step 2 [4-chloro-3-nitro-5-(trifluoromethyl)phenyl]methanol 4-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (1.66 g, 6.15 mmol) was dissolved in THF (20 mL), cooled to 0°C, and then dimethyl sulfideborane (9.24 mL, 18.46 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 72 hours, then quenched by gradually adding saturated NaHCO3 aqueous solution, and extracted with siRNA (×2). The organic layers were combined, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain 4-chloro-3-nitro-5-(trifluoromethyl)phenyl]methanol (1.31 g, 5.11 mmol, yield 83%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl3) δ / ppm: 7.94 (1H, s), 7.91 (1H, s), 4.84 (2H, s). Exchangeable protons disappear.

[0220] Step 3: 5-(bromomethyl)-2-chloro-1-nitro-3-(trifluoromethyl)benzene A 15 mL solution of [4-chloro-3-nitro-5-(trifluoromethyl)phenyl]methanol (1.31 g, 5.11 mmol) in DCM was cooled to 0°C, followed by the addition of triphenylphosphine (1.61 g, 6.13 mmol) and tetrabromomethane (1864.1 mg, 5.62 mmol). The reaction mixture was stirred overnight at room temperature, and then washed with saturated aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, and the solvent was removed by vacuum to obtain 5-(bromomethyl)-2-chloro-1-nitro-3-(trifluoromethyl)benzene (3.94 g, 5.07 mmol, 99% yield) as a yellow oil. 1 H-NMR (400MHz, CDCl3) δ / ppm: 7.97 (1 H, d, J = 2.0Hz), 7.95 (1H, d, J = 2.0Hz), 4. 52 (2H, s).

[0221] Step 4: 1-[4-chloro-3-nitro-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine Dimethylamine (2M in THF - 3.14 mL, 62.8 mmol) was added to 5-(bromomethyl)-2-chloro-1-nitro-3-(trifluoromethyl)benzene (500 mg, 0.6300 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum, and the crude product was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-100%. The fraction containing the product was loaded onto an SCX-2 column and flushed first with MeOH (20 mL), then with NH3 in MeOH (20 mL) to obtain 1-[4-chloro-3-nitro-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine (101 mg, 0.36 mmol, yield 57%) as a pale yellow oil. UPLC-MS (ES+, low acidity): 1.19 min, m / z 283.1 [M+H]+. 1 H-NMR (400MHz, CDCl3) δ / ppm: 7.91-7.90 (1H, m), 7.89-7.87 (1H, m), 3.50 (2H, s), 2.27 (6H, s).

[0222] Step 5: 4-[(dimethylamino)methyl]-2-nitro-6-(trifluoromethyl)aniline 1-[4-chloro-3-nitro-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine (101 mg, 0.36 mmol) was dissolved in 1,4-dioxane (1 mL) in a sealed tube, followed by the addition of NH3 (28% in H2O - 0.99 mL, 7.15 mmol). The reaction mixture was stirred overnight at 120°C, after which the second portion of NH3 (28% in H2O, 0.99 mL, 7.15 mmol) was added. The reaction mixture was left stirred overnight at 120°C. The crude product was filtered through a phase separator to obtain 4-[(dimethylamino)methyl]-2-nitro-6-(trifluoromethyl)aniline (94 mg, 0.36 mmol, 100% yield) as a yellow solid. UPLC-MS (ES+, low acidity) : 0.90 min, m / z 264.2 [M+H]+. 1H-NMR (400MHz, DMSO-d6) δ / ppm: 8.36 (1H, s), 7.95 (1H, s), 7.42 (2H, s), 3.78 (2H, s), 2.40 (6H, s).

[0223] Step 6: 5-[(dimethylamino)methyl]-3-(trifluoromethyl)benzene-1,2-diamine 4-[(dimethylamino)methyl]-2-nitro-6-(trifluoromethyl)aniline (94 mg, 0.36 mmol) was dissolved in SiO2 (10 mL) and EtOH (17 mL), and then palladium (10 wt.% (12.1 mg) on ​​carbon powder) was added under a nitrogen atmosphere. An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed, after which the mixture was stirred overnight under an H2 atmosphere. The crude product was filtered through Celite, and the solvent was removed under reduced pressure to obtain 5-[(dimethylamino)methyl]-3-(trifluoromethyl)benzene-1,2-diamine (77 mg, 0.33 mmol, yield 92%) as a yellow solid. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 6.81 (1H, s), 6.77 (1H, s), 5.15-5.00 (4H, m), 3.83 (2H, br s), 2.50 (6H, s, (under DMSO)). UPLC-MS (ES+, low acidity): 0.76 min, m / z 234.2 [M+H]+.

[0224] Using 1-methylpiperazine instead of dimethylamine in step 4, the intermediates shown in the table below were prepared in a similar manner. [Table 9]

[0225] Example 10. Synthesis of 3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzene-1,2-diamine [ka] Step 1: 2-Chloro-3-nitro-5-(trifluoromethyl)benzoic acid 2-(trifluoromethyl)pyridine-4-ol (1 g, 6.13 mmol) was dissolved in sulfuric acid (10.68 mL, 200.39 mmol), followed by the addition of nitric acid (fuming, 90% (1.7 mL, 40.08 mmol)). The reaction mixture was then heated to 90°C for 45 minutes, cooled to room temperature, and poured into ice water (250 mL). The product was filtered, washed with ice water (40 mL), and vacuum-dried to obtain 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (3.36 g, 12.48 mmol, 93% yield) as a white solid in 93% yield. UPLC-MS (ES-, low acidity): 1.46 min, m / z 268.1 [MH]-. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 8.73-8.70 (1H, m), 8.43-8.39 (1H, m). No interchangeable protons are observed.

[0226] Step 2 [2-chloro-3-nitro-5-(trifluoromethyl)phenyl]methanol Isobutyl chloroformate (3.41 mL, 26.31 mmol) is used in the following way: 4-methylmorpholine (4.82 mL, 43.85 mmol) and 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (2.36 g, 8.77 mmol) in DCM (70 mL). The reaction was added to a stirred solution under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature, and then the solvent was evaporated under reduced pressure. The crude product was dissolved in THF (50 mL) and gradually added at 0°C to a solution of NaBH4 (497.64 mg, 13.16 mmol) in H2O (50 mL). The reaction mixture was stirred at room temperature for 1 hour, then quenched by gradually adding saturated NH4Cl aqueous solution (100 mL), followed by extraction with DCM (2 × 100 mL). The combined organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography using a 0-50% siRNA / petroleum ether eluent to obtain [2-chloro-3-nitro-5-(trifluoromethyl)phenyl]methanol (1.21 g, 1.51 mmol, yield 17%) as a yellow oil. UPLC-MS (ES+ / -, low acidity): 1.63 min, m / znd. 1 H-NMR (400M Hz, DMSO-d6) δ / ppm: 8.13 (1H, s), 8.00 (1H, s), 4.93 (2H, s).

[0227] Step 3: 1-(bromomethyl)-2-chloro-3-nitro-5-(trifluoromethyl)benzene A 10 mL solution of [2-chloro-3-nitro-5-(trifluoromethyl)phenyl]methanol (1.21 g, 1.51 mmol) in DCM was cooled to 0°C, followed by the addition of triphenylphosphine (475 mg, 1.81 mmol) and tetrabromomethane (551 mg, 1.66 mmol). The reaction mixture was stirred overnight at room temperature, after which the second portion of triphenylphosphine (475 mg, 1.81 mmol) and tetrabromomethane (551 mg, 1.66 mmol) was added and the mixture was stirred for 4 hours. The reaction mixture was washed with saturated aqueous NaHCO3; the organic phase was separated and dried over Na2SO4, and the solvent was removed by vacuum to obtain 1-(bromomethyl)-2-chloro-3-nitro-5-(trifluoromethyl)benzene (2.71 g, 1.49 mmol, 99% yield) as a yellow oil. UPLC-MS (ES+ / -, low acidity): 1.26 min, m / z nd.

[0228] Step 4: 1-[2-chloro-3-nitro-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine Dimethylamine (2.74 mL, 54.95 mmol, 2M in THF) was added to 1-(bromomethyl)-2-chloro-3-nitro-5-(trifluoromethyl)benzene (1 g, 0.55 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then the solvent was removed by vacuum, and the crude product was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-20%. The fraction containing the product was loaded onto an SCX-2 column and flushed first with MeOH (10 mL), then with NH3 in MeOH (10 mL) to obtain 1-[2-chloro-3-nitro-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine (82 mg, 0.29 mmol, yield 53%) as an orange oil. UPLC-MS (ES+, low acidity): 1.07 min, m / z 283.1 [M +H]+. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 8.08-8.05 (1H, m), 7.94-7.90 (1H, m), 3.65 (2H, s), 2.34 (6H, s).

[0229] Step 5: 2-[(dimethylamino)methyl]-6-nitro-4-(trifluoromethyl)aniline 1-[2-chloro-3-nitro-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine (82 mg, 0.29 mmol) was dissolved in 1,4-dioxane (0.8100 mL) in a sealed tube, followed by the addition of NH3 (28% in H2O - 0.81 mL, 5.8 mmol). The reaction mixture was stirred overnight at 120°C. The crude product was filtered using a phase separator to obtain 2-[(dimethylamino)methyl]-6-nitro-4-(trifluoromethyl)aniline (76 mg, 0.29 mmol, 100% yield) as a yellow oil. UPLC-MS (ES+, low acidity): 1.11 min, m / z 264.2 [ M+H]+. 1H-NMR (400MHz, DMSO-d6) δ / ppm: 8.2 4 (1H, s), 8.12 (2H, s), 7.70 (1H, s), 3.66 (2H, br s), 2.23 (6H, s).

[0230] Step 6: 3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzene-1,2-diamine 2-[(dimethylamino)methyl]-6-nitro-4-(trifluoromethyl)aniline (75 mg, 0.28 mmol) was dissolved in ethyl acetate (5 mL) and ethanol (9 mL), followed by the addition of palladium (10 wt.% (10 mg) on ​​carbon powder) under a nitrogen atmosphere. An H2 balloon was attached to the reaction chamber, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 4 hours. The crude product was filtered through Celite, and the solvent was removed under reduced pressure to obtain 3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzene-1,2-diamine (66 mg, 0.28 mmol, 99% yield) as a yellow solid. UPLC-MS (ES+, low acidity): 0.91 min, m / z 234.2 [M+H]+. 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 6.78 (2H, s), 6.70 (2H, br s), 4.98 (4H, br s), 2.28 (6H, br s).

[0231] Example 11. Synthesis of N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl]methyl]propan-2-amine [ka] Step 1: N-[[3-bromo-5-(trifluoromethyl)phenyl]methyl]propan-2-amine 2-aminopropane (0.34 mL, 3.95 mmol) was added to a stirred solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (0.6 mL, 3.95 mmol) and MeOH (10 mL) under a nitrogen atmosphere at room temperature for 18 hours. Next, NaBH4 (224.3 mg, 5.93 mmol) was added, and the resulting mixture was stirred for 10 minutes and quenched with water (5 mL). The organic solvent was then removed by vacuum, and the remaining mixture was partitioned between water (50 mL) and toluene (50 mL). The aqueous layer was further extracted with toluene (50 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-10% MeOH / DCM eluent to obtain N-[[3-bromo-5-(trifluoromethyl)phenyl]methyl]propan-2-amine (665 mg, 2.25 mmol, yield 57%) as a yellow oil. UPLC-MS (ES+, low acidity): 1.13 min, m / z 295.9, 297.9 [M+H]+. 1 H NMR (400MHz, CDCl3) δ / ppm: 7.72 (1H, s), 7.66 (1H, s), 7.56 (1H, s), 3.84 (2H, s) , 2.86 (1H, septet, J = 6.4Hz), 1.12 (6H, d, J = 6.4Hz). No replaceable protons are observed.

[0232] Step 2: N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl]methyl]propan-2-amine N-[[3-bromo-5-(trifluoromethyl)phenyl]methyl]propan-2-amine (300 mg, 1.01 mmol), bis(pinacolato)diborone (283 mg, 1.11 mmol), KOAc (298.3 mg, 3.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (82.7 mg, 0.10 mmol), and 1,4-dioxane (10 mL) were stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, and the solvent was removed by vacuum. The residue was dissolved in DCM (10 mL), filtered through Celite, and washed with DCM (10 mL). The filtrate was vacuum concentrated, and the residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan]-2-yl)-5-(trifluoromethyl)phenyl]methyl]propan-2-amine (185 mg, 0.54 mmol, yield 53%) as a yellow oil. UPLC-MS (ES+, low acidity): 1.02 min, m / z 262.1 [ M-Pinacol +H]+; 1.41 min, m / z 344.3 [M+H]+. 1 H NM R (400MHz, CDCl3) δ / ppm: 7.96-7.93 (2H, m), 7.71 (1H, s), 3.85 (2H, s), 2.88 (1H, septet, J = 6.4Hz), 1.38 (12H, s), 1.13 (6H, d, J = 6.4Hz). No interchangeable protons were observed.

[0233] Example 12. Synthesis of [3-[(dimethylamino)methyl]-5-(trifluoromethyl)phenyl]boronic acid [ka] Step 1: [3-Bromo-5-(trifluoromethyl)phenyl]methanol Sodium borohydride (149.5 mg, 3.95 mmol) was added to a stirred solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (500 mg, 1.98 mmol) and MeOH (10 mL) at room temperature for 1 hour. The reaction mixture was poured into water (50 mL), and the resulting mixture was extracted with  (2 × 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and the solvent was removed under vacuum to obtain [3-bromo-5-(trifluoromethyl)phenyl]methanol (444 mg, 1.74 mmol, yield 88%) as a colorless oil. The product was used in the next step without further purification. UPLC-MS (E S+, low acidity): 1.68 min, m / z nd. 1 1H NMR (400MHz, CD) Cl3) δ / ppm: 7.74 (1H, s), 7.71 (1H, s), 7.59 (1H, s), 4.79 (2H, s). No exchangeable protons are observed.

[0234] Step 2: 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene [3-Bromo-5-(trifluoromethyl)phenyl]methanol (444 mg, 1.74 mmol) was added to a stirred solution of triphenylphosphine (685 mg, 2.61 mmol), tetrabromomethane (866 mg, 2.61 mmol), and THF (20 mL) at -10°C under a nitrogen atmosphere. The reaction mixture was heated to room temperature and stirred for 2 hours. It was then vacuum concentrated and partitioned between water (100 mL) and DCM (100 mL). The organic layer was separated, dried over Na₂SO₄, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-50% siRNA / petroleum ether eluent to obtain 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (469 mg, 1.48 mmol, yield 85%) as a yellow oil. UPLC-MS (ES+, low acid degree): 2.06 min, m / z nd. 1H NMR (400MHz, CDCl3) δ / ppm: 7.76-7.72 (2H, m), 7.60 (1H, s), 4.47 (2H, s).

[0235] Step 3: 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (469 mg, 1.48 mmol) was added to a stirred solution of dimethylamine (2 M - 3 mL, 6 mmol in THF) under a nitrogen atmosphere at room temperature and stirred for 10 minutes. The solvent was removed by vacuum, and the residue was partitioned between water (20 mL) and DCM (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-10% MeOH / DCM eluent to obtain 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine (337 mg, 1.19 mmol, yield 81%) as a yellow oil. UPLC-MS (ES+, low acidity) ): 1.13 min, m / z 281.9, 283.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 7.70-7.67 (2H, m), 7.54 (1H, s), 3.46 (2H, s), 2.27 (6H, s).

[0236] Step 4 [3-[(dimethylamino)methyl]-5-(trifluoromethyl)phenyl]boronic acid 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethaneamine (337 mg, 1.19 mmol), bis(pinacolato)diborone (334 mg, 1.31 mmol), KOAc (352 mg, 3.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (98 mg, 0.1200 mmol), and 1,4-dioxane (10 mL) were stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was suspended in DCM (10 mL), filtered through Celite, and washed with DCM (10 mL). The filtrate was vacuum concentrated, and the residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain [3-[(dimethylamino)methyl]-5-(trifluoromethyl)phenyl]boronic acid (109 mg, 0.44 mmol, yield 37%) as a yellow oil. UPLC-MS (ES+, low acidity): 0.93 min, m / z 248.1 [M +H] + .

[0237] Example 13. Synthesis of 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] Step 1: 2-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (0.09 g, 0.11 mmol) was added under a nitrogen atmosphere to a stirred solution of bis(pinacolato)diborone (0.3 g, 1.18 mmol), 4-bromo-2-ethylpyridine (0.2 g, 1.07 mmol), KOAc (0.16 g, 1.61 mmol), and 1,4-dioxane (20 mL). The reaction mixture was heated to 100 °C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was dissolved in DCM (50 mL), filtered through Celite, and washed with DCM (10 mL). The filtrate was vacuum concentrated to obtain 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250 mg, 1.0725 mmol, yield 99.765%) as black oil. The product was used in the next step without further purification. UPLCMS (ES+, low Acidity): 0.83 min, m / z 151.9 [M-Pinacol] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 8.57 (1H, d, J = 9.2Hz), 7.54 (1H, d, J = 6.4Hz), 7.47 (1H, d, J = 9.2Hz), 2.85 (2H, q, J = 8.0Hz), 1.39 (12H, s) , 1.33 (3H, t, J = 8.0Hz).

[0238] Using a suitable (hetero)aryl bromide instead of 4-bromo-2-ethylpyridine, the intermediates shown in the table below were prepared in a similar manner. [Table 10]

[0239] Example 14. Synthesis of 1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] n-butyllithium solution (0.4 mL, 1 mmol) was added at 0°C under a nitrogen atmosphere to a stirred solution of 1-ethyl-3-methylpyrazole (0.1 mL, 0.91 mmol) and THF (5 mL). The mixture was heated to 25°C for 1 hour, then cooled to -78°C. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22 mL, 1.09 mmol) was added, and after 10 minutes at -78°C, the reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with water, and the resulting mixture was reduced under vacuum. The residue was azeotropically removed with toluene to obtain 1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrazole (214 mg, 0.91 mmol, yield 100%) as an off-white solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 0.83 min, m / z 154.6 [M+H] + .

[0240] Example 15. Synthesis of 1-cyclopropyl-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Step 1: 5-Bromo-1-cyclopropyl-3-ethyl-pyrazole 2-Cyclopropyl-5-ethyl-pyrazole-3-ol (730 mg, 4.8 mmol) was suspended in PBr3 (3.05 mL, 16.79 mmol) containing MeCN (3 mL) in a resealable vial. The vial was sealed and the reaction mixture was heated to 150 °C for 1.5 hours. After cooling to room temperature, the reaction mixture separated into two layers; the upper layer (MeCN) was quenched with ice-cold saturated NaHCO3 aqueous solution to a pH of approximately 7-8. The aqueous layer was separated and extracted with RINKAN (3×); the organic compounds were combined, passed through a phase separator, dried, and reduced under vacuum to obtain 5-bromo-1-cyclopropyl-3-ethyl-pyrazole (340 mg, 1.58 mmol, yield 33%) as an orange oil. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.75 min, m / z 214.9, 216.9 [M+H] + .

[0241] Step 2: 1-Cyclopropyl-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (129.1 mg, 0.16 mmol) was added to a stirred solution of bis(pinacolato)diborone (401.4 mg, 1.58 mmol), 5-bromo-1-cyclopropyl-3-ethyl-pyrazole (340 mg, 1.58 mmol), potassium acetate (310.3 mg, 3.16 mmol), and 1,4-dioxane (10 mL) under an inert atmosphere at room temperature. The reaction mixture was heated to 85 °C for 1 hour, cooled to room temperature, and the solvent was removed by vacuum. The residue was dissolved in DCM (20 mL), filtered through Celite, and the filtrate was washed with DCM (10 mL). The filtrate was vacuum-concentrated to obtain 1-cyclopropyl-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (414 mg, 1.58 mmol, 100% yield) as a black oil. The compound was used in the next step without further purification. UPLCMS (ES+, low acidity): 1.05 min, m / z 180.7 [M-pinacol] + .

[0242] Using the appropriate starting materials from Step 1, the intermediates shown in the table below were prepared in a similar manner. [Table 11]

[0243] Synthesis of the Compounds Disclosed Example 16. Synthesis of 5-[3-[4-[3-(trifluoromethyl)phenyl]-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 12) [ka] Step 1 [2-Oxo-2-[3-(trifluoromethyl)phenyl]ethyl]6-[(7-Oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylate 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (200 mg, 0.59 mmol) and K2CO3 (244 mg, 1.76 mmol) were dissolved in dry DMF (5 mL) and treated little by little with 3-(trifluoromethyl)phenacyl bromide (173 mg, 0.65 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, after which the second portion of 3-(trifluoromethyl)phenacyl bromide (172 mg, 0.65 mmol) was added and the reaction mixture was stirred for 1 hour. The mixture was left as is. Water (15 mL) was added, and the product was extracted with DCM (×3). The combined organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was purified by column chromatography using siRNA / petroleum as the eluent with a gradient of 0 to 100%, yielding 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl]6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylate (55 mg, 0.10 mmol, yield 18%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.78 min, m / z 527.4 [M+H] + .

[0244] Step 2: 5-[3-[4-[3-(trifluoromethyl)phenyl]-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one [2-Oxo-2-[3-(trifluoromethyl)phenyl]ethyl]6-[(7-Oxo-6,8-dihydro-5H-1,8-naphthyrizin-4-yl)oxy]chroman-3-carboxylate (55 mg, 0.10 mmol) and ammonium acetate (1.21 g, 15.67 mmol) were mixed in a sealed vial, and the reaction mixture was heated at 130°C for 8 hours. Water was added, and the product was extracted with SiO(×3). The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-100%, followed by 0-5% MeOH / DCM, to obtain 5-[3-[4-[3-(trifluoromethyl)phenyl]-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 12) as a white solid. UPLC-MS (ES+, most Final purity) 3.17 min, m / z 507.3 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 12.51 (0.10H, br s), 12. 26 (0.90H, br s), 10.46 (1H, s), 8.10-7.99 (2H, m), 7.95 (1H, d, J = 6.0Hz), 7.82 (1H, s), 7.60-7.48 (2H, m), 7.02 (1H, s), 6.94-6.8 7 (2H, m), 6.26 (1H, d, J = 5.6Hz), 4.55-4.4 5 (1H, m), 4.19-4.09 (1H, m), 3.46-3.38 (1H , m), 3.30-3.20 (1H, m), 3.17-3.08 (1H, m), 2.93 (2H, t, J = 7.6 Hz), 2.56-2.53 (m, 2H).

[0245] Example 17. Synthesis of 5-[3-[4-(3-methoxyphenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 13) [ka] Step 1 [2-(3-methoxyphenyl)-2-oxo-ethyl]6-[(7-Oxo So-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylate 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (200 mg, 0.59 mmol) and 2-bromo-1-(3-methoxyphenyl)ethanone (135 mg, 0.59 mmol) were dissolved in dry MeCN (10 mL), cooled to 0°C, and then DIPEA (0.15 mL, 0.88 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After this time, ice water was added, and then the mixture was extracted with siRNA (x3) and DCM (x2). The combined organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-100%, yielding [2-(3-methoxyphenyl)-2-oxo-ethyl]6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylate (217 mg, 0.44 mmol, yield 76%) as a white solid. UPLC-MS (ES+, low acidity): 1.69 min, m / z 489.3 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 10.46 (1H, s), 7.95 (1H, d, J = 6.0Hz), 7.59-7.55 (1H, m), 7.51-7.43 (2H, m), 7.27 (1H, ddd, J = 8. 2Hz, 2.6Hz, 0.8Hz), 7.01 (1H, d, J = 2.8Hz), 6.93-6.85 (2H, m), 6.25 (1H, d, J = 5.6Hz), 5.57 (2H, s), 4.44 (1H, dd, J = 10.8Hz, 3.2H z), 4.24 (1H, dd, J = 10.8 Hz, 8.0Hz), 3.83 (3H, s), 3.31-3.25 (1H, m), 3.10-3.05 (2H, m ), 2.92 (2H, t, J = 8.0Hz), 2.53 (2H, t, J = 8.0Hz, (partly under DMSO)).

[0246] Step 2: 5-[3-[4-(3-methoxyphenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one [2-(3-methoxyphenyl)-2-oxo-ethyl]6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylate (98 mg, 0.20 mmol) and ammonium acetate (309 mg, 4.01 mmol) were mixed in a sealed vial, followed by the addition of xylene (1 mL), and the mixture was heated at 150°C for 30 minutes. Water was added, and the product was extracted with ELISA (×3). The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was loaded onto an SCX-2 column and flushed first with MeOH (10 mL), then with NH3 in MeOH (10 mL) to elute the product. The fractions containing the product were combined and purified by column chromatography using MeOH / DCM with a gradient of 0-5% as the eluent. The fraction containing the product was re-purified by reverse-phase column chromatography using acetonitrile + 0.1% formic acid / water + 0.1% formic acid as the eluent with a gradient of 5-100%, yielding 5-[3-[4-(3-methoxyphenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (compound 13) (8 mg, 0.017 mmol, yield 9%) as a white solid. UPLC-MS (ES+, final purity) 2.76 min, m / z 469.3 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 12.29 (br s, 0.2H ), 12.09 (br s, 0.8H), 10.46 (s, 1H). 7.95 ( d, J = 5.6Hz, 1H), 7.61 (d, J = 2.0Hz, 0.8H), 7.35-7.28 (m, 2H), 7.25-7.19 (m, 1.2H), 7. 01 (d, J = 2.4Hz, 1H), 6.94-6.85 (m, 2H), 6. 84-6.78 (m, 0.2H), 6.74 (ddd, J = 8.4Hz, 2.8Hz, 1.2Hz, 0.8H), 6.27 (d, J = 5.6Hz, 1H), 4 .53-4.47 (m, 1H), 4.15-4.09 (m, 1H), 3.80 ( s, 0.6H), 3.77 (s, 2.4H), 3.45-3.35 (m, 1H) , 3.30-3.19 (m, 1H), 3.16-3.06 (m, 1H), 2.9 3 (t, J = 7.2 Hz, 2H), 2.54-2.52 (m, 2H).

[0247] The compounds shown in the table below were prepared in the same manner as in Example 17, using a suitable 2-bromo-1-arylethanone instead of the 2-bromo-1-(3-methoxyphenyl)ethane in Step 1. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5]

[0248] In Step 1, replace 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid with the appropriate 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]chroman-3-carboxylic acid (Examples) Using 5), and replacing 2-bromo-1-(3-methoxyphenyl)ethane in step 2 with 2-bromo-1-phenylethane, the compounds shown in the table below were prepared in a similar manner. [Table 13]

[0249] Example 18. Synthesis of 5-[3-[4-(2-methoxy-4-pyridyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 19) [ka] Step 1: 5-[3-[4-(2-methoxy-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one 5-[3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (100 mg, 0.18 mmol), 2-methoxypyridine-4-boronic acid (32.1 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (14.3 mg, 0.020 mmol), K2CO3 (72.6 mg, 0.52 mmol), 1,4-dioxane (5 The reaction mixture (mL) and water (1 mL) were combined under a nitrogen atmosphere and heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-10% MeOH / DCM eluent to obtain 5-[3-[4-(2-methoxy-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (96 mg, 0.16 mmol, yield 91%) as an orange oil. UPLC-MS (ES+, low acidity): 1.82 min, m / z 600.5 [M+H] + .

[0250] Step 2: 5-[3-[4-(2-methoxy-4-pyridyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizine-2-one Trifluoroacetic acid (1 mL, 13.06 mmol) was added at room temperature to a stirred solution of 5-[3-[4-(2-methoxy-4-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (97 mg, 0.16 mmol) in DCM (4 mL) and EtOH (0.1 mL). The mixture was stirred for 48 hours, after which the solvent and TFA were removed by vacuum. The residue was loaded onto an SCX-2 column and flushed first with MeOH (20 mL), then with NH3 in MeOH (20 mL) to elute the product. The fractions containing the product were combined and concentrated by vacuum. The residue was purified by column chromatography using a 0-10% MeOH / DCM eluent to obtain 5-[3-[4-(2-methoxy-4-pyridyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizin-2-one (21 mg, 0.045 mmol, yield 28%) as a white solid. UPLC-MS (ES+, low acidity): 2.66 min, m / z 470.3 [M+H] + . 1 1H NMR (400MHz, DMSO-d 6) δ / ppm: 12.34 (1H, s), 10.47 (1H, s), 8.07 (1H, d, J = 5.2Hz), 7.96 (1H, d, J = 5.6Hz), 7.87 (1H, d, J = 6.4Hz), 7.34-7.31 (1H, m), 7.10 (1H, d, J = 8.0Hz), 7.03-7.00 (1H, m), 6.95-6.87 (2H, m), 6.27 (1H, d, J = 6.0Hz), 4.54-4.48 (1H, m), 4.14 (1H, t, J = 10.0Hz), 3.88-3.83 (3H, m), 3.46-3.39 (1H, m), 3.28 -3.09 (2H, m), 2.94 (2H, t, J = 7.6Hz), 2.62 -2.57 (2H, m, (below the DMSO peak).

[0251] The compounds shown in the table below were prepared in the same manner as in Example 18, using an appropriate boronic acid / pinacol ester instead of 2-methoxypyridine-4-boronic acid in Step 1. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6]

[0252] Example 19. 5-[3-[4-(2,5-dimethylpyrazole-3-yl)-1H-yl Synthesis of midazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 106) [ka] Step 1: 3-[4-(2,5-dimethylpyrazole-3-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (200 mg, 0.47 mmol), K2CO3 (195 mg, 1.41 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (104.4 mg, 0.47 mmol), 1,4-dioxane (4 mL), and water (1 mL) were combined and stirred at room temperature under a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (38.4 mg, 0.050 mmol) was added, and the reaction mixture was heated to 100 °C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 25-100% siRNA / petroleum ether eluent to obtain 3-[4-(2,5-dimethylpyrazole-3-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (143 mg, 0.32 mmol, yield 69%) as an orange oil. UPLC-MS (ES+, low acidity): 1.74 min, m / z 441.8 [M+H] + .

[0253] Step 2: 5-[3-[4-(2,5-dimethylpyrazole-3-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one Potassium tert-butoxide (40 mg, 0.36 mmol) was added to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (53.9 mg, 0.32 mmol) and 3-[4-(2,5-dimethylpyrazole-3-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (143 mg, 0.32 mmol) in DMF (2 mL), and the reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature, the solvent was reduced under vacuum, and the residue was partitioned between RINKAN and water. The organic layer was washed with saturated brine, separated, dried in a phase separator, and the solvent was reduced under vacuum. The residue was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 25-100%, yielding 5-[3-[4-(2,5-dimethylpyrazole-3-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (83 mg, 0.14 mmol, yield 44%) as a colorless rubber. UPLC-MS (ES+, low acidity): 1.83 min, m / z 587.5 [M+H ] + .

[0254] Step 3: 5-[3-[4-(2,5-dimethylpyrazole-3-yl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one Trifluoroacetic acid (0.54 mL, 7.08 mmol) was added to a stirred solution of 5-[3-[4-(2,5-dimethylpyrazole-3-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (83 mg, 0.14 mmol) and DCM (2 mL) in a sealed vial, and the mixture was heated at 40°C for 18 hours. The solvent was removed under reduced pressure, and the residue was loaded onto an SCX-2 column. The product was eluted by flushing first with MeOH (10 mL) and then with NH3 in MeOH (10 mL). The residue was purified by column chromatography using a MeOH / DCM gradient of 1–8% as the eluent. The fractions containing the product were combined, the solvent was removed by vacuum, and the residue was pulverized in MeCN / Et2O to obtain a white solid. This solid was filtered and dried to obtain 5-[3-[4-(2,5-dimethylpyrazole]-3-yl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (33.5 mg, 0.073 mmol, yield 52%). UPLC-MS (ES+, final purity): 2.62 min, m / z 457.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.30 (0.13H, s), 12.26 (0.87H, s), 10.46 (1H, s), 7.96 (1H, d, J = 6.0Hz), 7.42 (0.87 H, d, J = 1.6Hz), 7.13 (0.13H, d, J = 1.6Hz), 7.01-6.98 (1H, m), 6.94-6.81 (2H, m), 6.26 -6.25 (1.13H, m), 6.14 (0.87H, s), 4.53-4.44 (1H, m), 4.13 (1H, t, J = 10.4Hz), 3.91 (2.61H, s), 3.80 (0.39H, s), 3.45-3.35 (1H, m) , 3.27-3.06 (2H, m), 2.93 (2H, t, J = 8.0Hz) , 2.53 (2H, t, J = 8.0Hz, (partially under DMSO), 2.15 (2.61 H, s), 2.11 (0.39 H, s).

[0255] The compounds shown in the table below were prepared in the same manner as in Example 19, using an appropriate boronic acid / pinacol ester instead of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step 1. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7]

[0256] Example 20. Synthesis of 5-[3-(4-tetrahydropyran-4-yl-1H-imidazole-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 132) [ka] Step 1: 3-[4-(3,6-dihydro-2H-pyran-4-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (108.7 mg, 0.52 mmol), 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (220 mg, 0.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (42.2 mg, 0.050 mmol), potassium carbonate (214.4 mg, 1.55 mmol), 1,4-dioxane (4 mL), and water (1 mL) were combined in a sealable vial under a nitrogen atmosphere at room temperature. The vial was sealed, and the reaction mixture was heated to 80°C and stirred for 2 hours. It was then cooled to room temperature and the solvent was removed by vacuum. The residue was dissolved in DCM (20 mL), filtered through Celite, and the filtered solid was collected in DCM (10 mL). The sample was washed with 0-100% siRNA / petroleum ether. The residue was purified by column chromatography using 0-100% siRNA / petroleum ether as the eluent to obtain 3-[4-(3,6-dihydro-2H-pyran-4-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (149 mg, 0.35 mmol, yield 67%) as a yellow solid. UPLCMS (ES+, low acidity): 1.53 min, m / z 429.7 [M+H] + .

[0257] Step 2: 3-[4-tetrahydropyran-4-yl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol 3-[4-(3,6-dihydro-2H-pyran-4-yl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (149 mg, 0.35 mmol) was stirred in siRNA (10 mL) under a nitrogen atmosphere at room temperature. Palladium (10 wt.% on carbon powder, dry (20 mg)) was added, a hydrogen balloon was attached to the reaction, and the vacuum / hydrogen cycle was performed three times. Then, the mixture was stirred under a hydrogen atmosphere for 18 hours. Next, the reaction mixture was filtered through a Celite plug, and the plug was washed with MeOH (10 mL). The filtrate was concentrated under vacuum to obtain 3-[4-tetrahydropyran-4-yl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (95 mg, 0.22 mmol, yield 63%) as a yellow solid. The compound was used directly in the next step without further purification. UPLC-MS (ES+, low acidity): 1.49 min, m / z 431.7 [M+H] + . Step 3: 5-[3-(4-tetrahydropyran-4-yl-1H-imidazole-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one Potassium tert-butoxide (75.4 mg, 0.67 mmol) was added to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (36.7 mg, 0.22 mmol) and 3-[4-tetrahydropyran-4-yl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (95 mg, 0.22 mmol) in DMF (2 mL). The reaction mixture was sealed in a tube and heated at 90°C for 60 hours. The reaction mixture was cooled to room temperature, reduced under vacuum, and partitioned between ethyl acetate and water. The organic matter was washed with saturated brine, separated, dried in a phase separator, and reduced under vacuum. The residue was purified by column chromatography using MeOH / DCM with a gradient of 1-10% as the eluent. The fractions containing the product were combined and re-purified by preparative HPLC (initial method). The fractions containing the product were combined, the solvent was removed under reduced pressure, and the mixture was loaded onto an SCX column. It was flushed first with MeOH, then with 1.0 M MeOH / NH3 to obtain 5-[3-(4-tetrahydropyran-4-yl-1H-imidazole-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizine-2-one (5 mg, 0.011 mmol, yield 5%) as a white solid. UPLC-MS (ES+, final purity): 2.36 min, m / z 447.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6+CF3CO2D) δ / ppm: 14.11 (1 H, s), 10.65 (1H, s), 8.00 (1H, d, J = 6.0Hz), 7.46 (1H, s), 7.03 (1H, d, J = 2.8Hz), 7.00-6.91 (2H, m), 6.30 (1H, d, J = 6.0Hz), 4.51 (1H, dd, J = 10.9Hz, 3.1Hz), 4.34 (1H, dd, J = 11.0Hz, 8.1Hz, 1H), 3.93 (2H, ddd, J = 11. 5Hz, 4.5Hz, 2.0Hz), 3.83-3.73 (1H, m), 3.44 (2H, td, J = 11.7Hz, 2.1Hz), 3.30-3.23 (2H, m), 3.01-2.89 (3H, m), 2.56 (2H, dd, J = 8.4Hz, 7.0Hz), 1.92-1.82 (2H, m), 1.63 (2H, qd (J = 12.1Hz, 4.4Hz).

[0258] Example 21. 5-[3-[5-(3-methoxy-2-thienyl)-1H-imidazole Synthesis of -2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 122) [ka] Step 1: tert-butyl N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]carbamate and tert-butyl N-[2-(3-methoxy-2-thienyl)-2-oxo-ethyl]carbamate n-butyllithium solution (3.5 mL, 8.76 mmol) was added to a stirred solution of 3-methoxythiophene (0.87 mL, 8.76 mmol) and THF (20 mL) under a nitrogen atmosphere at -78°C. The mixture was stirred at -78°C for 20 minutes, then heated to 0°C for 20 minutes, and then cooled to -78°C. Tert-butyl N-[2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (477.9 mg, 2.19 mmol) was added. After 1 hour at -78°C, the reaction mixture was heated to room temperature and stirred for 18 hours. The reaction mixture was then poured into water (100 mL), and the resulting mixture was extracted with SiO2 (2 × 100 mL). The combined organic layer was dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-100% siRNA / petroleum ether eluent to obtain tert-butyl N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]carbamate (93 mg, 0.34 mmol, yield 16%) and tert-butyl N-[2-(3-methoxy-2-thienyl)-2-oxo-ethyl]carbamate (170 mg, 0.63 mmol, yield 29%) as yellow oil.

[0259] N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]carbamate:UPLCMS (ES+, low acidity): 1.62 min, m / z 294.0 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 7.37 (1H, d, J = 1.6Hz), 6.67 (1H, d, J = 1.6Hz), 5.39 (1 H, br s), 4.53-4.52 (2H, m), 3.83 (3H, s), 1 .45 (9H, s).

[0260] N-[2-(3-methoxy-2-thienyl)-2-oxo-ethyl]carbamate:UPLCMS (ES+, low acidity): 1.60 min, m / z 272.0 [M+H]+, 294.0 [M+Na] + .1 1H NMR (400MHz, CDCl3) δ / ppm : 7.59 (1H, d, J = 5.6Hz), 6.86 (1H, d, J = 5.6Hz), 5.56 (1H, br s), 4.52-4.50 (2H, m), 4.00 (3H, s), 1.47 (9H, s).

[0261] Step 2: 2-amino-1-(4-methoxy-2-thienyl)ethanone hydrochloride Hydrogen chloride (0.26 mL, 4 M in 1.03 mmol dioxane) was added at room temperature to a stirred solution of tert-butyl, N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]carbamate (93 mg, 0.34 mmol), and DCM (5 mL). The reaction mixture was stirred for 18 hours, after which the solvent was removed by vacuum to obtain 2-amino-1-(4-methoxy-2-thienyl)ethanone hydrochloride (71 mg, 0.34 mmol, 100% yield) as a yellow solid, which was used in the next step without further purification. UPLCMS (ES+, low acidity), 0.47 min, m / z 171.9 [M+H] + .

[0262] Step 3 N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizin-4-yl)oxy]chroman-3-carboxamide Propylphosphonic anhydride (0.31 mL, 0.51 mmol) was added to a stirred solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (116.4 mg, 0.34 mmol), 2-amino-1-(4-methoxy-2-thienyl)ethanone hydrochloride (71 mg, 0.34 mmol), triethylamine (0.1 mL, 0.68 mmol), and THF (5 mL). The reaction mixture was heated to 65°C and stirred for 18 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed by vacuum. The residue was partitioned between water (50 mL) and DCM (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide (52 mg, 0.11 mmol, yield 31%) as a white solid. UPLCMS (ES+, low acidity): 1.47 min, m / z 494.1 [M+H] + .

[0263] Step 4 5-[3-[5-(3-methoxy-2-thienyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide (52 mg, 0.11 mmol) and ammonium acetate (243.7 mg, 3.16 mmol) were dissolved in butyric acid (2 mL, 21.88 mmol) in a resealable vial. This mixture was sealed and heated at 175°C for 2 hours. The reaction mixture was evaporated to dryness, then treated with aqueous K2CO3 solution and extracted with DCM (15 ml). The organic layer was passed through a phase separator and then evaporated to dryness. The residue was chromatographically treated by preparative LC-MS to obtain 5-[3-[5-(4-methoxy-2-thienyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizine-2-one (8 mg, 0.016 mmol, yield 15%) as an off-white solid product. UPLC-MS (ES+, final purity): 2.80 min, m / z 475.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 10.67 (1H, s), 8.05-7.91 (2H, m), 7.69 (1H, d, J = 1.5 Hz), 7.25 (1H, d, J = 1.7 Hz), 7.05 (1H, d, J = 2 .5 Hz), 7.02-6.88 (2H, m), 6.76 (1H, d, J = 1.8 Hz), 6.32 (1H, d, J = 6.0 Hz), 4.56 (1H, d d, J = 10.9Hz, 3.2Hz), 4.35 (1H, dd, J = 11.0 Hz, 8.6Hz), 3.79 (3H, s), 3.87-3.69 (1H, m) , 3.35-3.23 (2H, m), 2.95 (2H, t, J = 7.7Hz) , 2.60-2.53 (2H, m).

[0264] The compounds listed in the table below were prepared in the same manner as in Example 21, using appropriate reagents instead of tert-butyl N-[2-(4-methoxy-2-thienyl)-2-oxo-ethyl]carbamate in Step 2. [Table 16]

[0265] Example 22. Synthesis of 5-[3-[4-(3,3-dimethylbutyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 115) [ka] Step 1: 3-[4-(3,3-dimethylbuta-1-inyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol

[0266] Tetrakis(triphenylphosphine)palladium(0) (54.3 mg, 0.05 mmol) was added at room temperature under a nitrogen atmosphere to a stirred mixture of 3-[4-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (200 mg, 0.47 mmol), 3,3-dimethyl-1-butyne (0.17 mL, 1.41 mmol), copper(I) iodide (9.0 mg, 0.05 mmol), K2CO3 (130 mg, 0.94 mmol), monoglyceride (2 mL), and water (0.5 mL) in a resealable vial. The vial was sealed, and the reaction mixture was heated to 90°C and stirred for 18 hours. After this, the reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was dissolved in DCM, filtered through a Celite plug, and the filtered solid was washed with DCM (10 mL). The filtrate was diluted with DCM (50 mL), the solution was washed with saturated NaHCO3 aqueous solution (10 mL) and brine (50 mL), dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-10% as the eluent to obtain 3-[4-(3,3-dimethylbuto-1-inyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (156.5 mg, 0.37 mmol, yield 78%) as a yellow solid. UPLC-MS (ES+, low acidity): 2.04 min, m / z 427.6 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ / ppm: 7.13 (1H, s), 6.73 (1H, d, J = 9.2Hz), 6.64-6.60 (1H, m), 6.59-6.56 (1H, m), 5.37 (2H, s), 4.69 (1H, s), 4.43-4.37 (1H, m), 4.07 (1H, t, J = 10.0Hz), 3.60-3. 55 (2H, m), 3.46-3.27 (2H, m), 2.95-2.88 (1 H, m), 1.32 (9H, s), 0.95-0.88 (2H, m), 0.00 (9H, s).

[0267] Step 2: 3-[4-(3,3-dimethylbutyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol 3-[4-(3,3-dimethylbuto-1-inyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (233 mg, 0.55 mmol) was stirred in MeOH (10 mL) under a nitrogen atmosphere at room temperature, followed by the addition of palladium (10 wt.%, dry on carbon powder (30 mg)). An H2 balloon was attached to the reaction chamber, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 18 hours. The crude product was filtered through Celite, washed with MeOH (10 mL), and the filtrate was concentrated under vacuum to obtain 3-[4-(3,3-dimethylbutyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (170 mg, 0.39 mmol, yield 72%) as a yellow solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.76 min, m / z 431.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 6 .77 (1H, s), 6.67 (1H, d, J = 8.8Hz), 6.61 (1H, dd, J = 8.8Hz, 2.4Hz), 6.56 (1H, d, J = 2. 4Hz), 5.24-5.18 (2H, m), 4.33-4.27 (1H, m), 4.05 (1H, t, J = 10.8Hz), 3.57-3.52 (2H, m) , 3.43-3.36 (1H, m), 3.30-3.21 (1H, m), 2.8 6-2.79 (1H, m), 2.57-2.51 (2H, m), 1.59-1.53 ​​(2H, m), 0.97 (9H, s), 0.96-0.91 (2H, m), 0.00 (9H, s). No exchangeable protons are observed.

[0268] Step 3: 5-[3-[4-(3,3-dimethylbutyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one Potassium tert-butoxide (132.9 mg, 1.18 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (65.6 mg, 0.39 mmol), 3-[4-(3,3-dimethylbutyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (170 mg, 0.39 mmol), and DMF (2 mL) in a sealed vial. The vial was sealed, and the reaction mixture was heated to 80°C and stirred for 72 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was partitioned between water (20 mL) and DCM (20 mL). The organic layer was separated and passed through a phase separator, and the solvent was removed by vacuum. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-5% as the eluent to obtain 5-[3-[4-(3,3-dimethylbutyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (116 mg, 0.20 mmol, yield 51%) as a yellow solid. UPLCMS (ES+, low acidity): 1.76 min, m / z 577.5 [M+H]+.

[0269] Step 4 5-[3-[4-(3,3-dimethylbutyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one Trifluoroacetic acid (0.5 mL, 6.53 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 5-[3-[4-(3,3-dimethylbutyl)-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (116 mg, 0.20 mmol) and DCM (2 mL) in a sealable vial. The vial was sealed, and the reaction mixture was heated to 40°C and stirred for 18 hours. After this time, the reaction mixture was cooled to room temperature, the solvent was removed by vacuum, and the residue was loaded onto an SCX-2 column using a minimum amount of MeOH. The product was eluted by passing MeOH (10 mL) through the column, followed by elution through NH3 in MeOH (10 mL). The product-containing fraction was vacuum-concentrated, and the residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain 5-[3-[4-(3,3-dimethylbutyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizine-2-one (10 mg, 0.022 mmol, yield 11%) as a white solid. UPLC-MS (ES+, final purity): 2.94 min. m / z 447.2 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ / ppm: 11.67 (0.5H, s), 11.58 (0.5H, s), 10 .45 (1H, s), 7.95 (1H, d, J = 5.6Hz), 6.99-6 .97 (1H, m), 6.93-6.85 (2H, m), 6.76 (0.5H, s), 6.49 (0.5H, s), 6.26 (1H, d, J = 5.6Hz), 4.46-4.40 (1H, m), 4.02 (1H, t, J = 10.8Hz), 3.29-3.23 (1H, m), 3.18-3.10 (1H, m), 3.06 -2.99 (1H, m), 2.93 (2H, t, J = 7.2Hz), 2.55 -2.50 (2H, m, (under DMSO)), 2.44-2.36 (2H, m), 1.50-1.43 (2H, m), 0.93-0.91 (9H, m).

[0270] Example 23. Synthesis of 5-[3-[3-[2-(trifluoromethyl)phenyl]-1H-pyrazole-5-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 35) [ka] Step 1: N-Methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide Propylphosphonic anhydride (50% in ethyl phosphate - 1.31 mL, 2.2 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (500 mg, 1.47 mmol), N,O-dimethylhydroxylamine hydrochloride (158 mg, 1.62 mmol), triethylamine (0.31 mL, 2.2 mmol), and THF (100 mL). The reaction mixture was heated to 65°C and stirred for 18 hours, then cooled to room temperature and the solvent was removed by vacuum. The residue was partitioned between water (100 mL) and DCM (100 mL). The organic layer was separated, dried over Na₂SO₄, filtered, and the solvent was removed by vacuum. The crude product was purified by column chromatography using a 0-100% siRNA / petroleum ether eluent to obtain N-methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide (337 mg, 0.88 mmol, yield 60%) as a white solid. UPLC-MS (ES+, low acidity): 1.39 min, m / z 384.3 [M+H] + . 1 1H NMR (400MHz, CDCl3) δ / ppm: 8.13 (1H, s), 7.99 (1H, d, J = 6.0Hz), 6.92-6.89 (1H, m), 6.87-6.83 (2H, m), 6.32 (1H, d, J = 6.0Hz), 4.48-4 .43 (1H, m), 4.06 (1H, t, J = 10.4Hz), 3.79 (3H, s), 3.45-3.35 (1H, m), 3.26 (3H, s), 3.23-3.14 (1H, m), 3.08 (2H, t, J = 7.2Hz), 2.9 3-2.86 (1H, m), 2.72 (2H, t, J = 7.2Hz).

[0271] Step 2: 5-[3-[3-[2-(trifluoromethyl)phenyl]propa-2-inoyl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one n-butyllithium solution (2.5 M in hexane - 0.35 mL, 0.88 mmol) was added dropwise to a stirred solution of 2-ethynyl-α,α,α-trifluorotoluene (0.12 mL, 0.88 mmol) in THF (20 mL) under a nitrogen atmosphere at -78°C. After stirring for 30 minutes, a solution of N-methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide (168 mg, 0.44 mmol) in THF (10 mL) was gradually added, and the resulting reaction was stirred at -78°C for 1 hour. After that, it was warmed to room temperature and quenched with saturated NH4Cl aqueous solution (100 mL). The mixture was extracted with siRNA (2 × 50 mL), the combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain 5-[3-[3-[2-(trifluoromethyl)phenyl]propa-2-inoyl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (163 mg, 0.33 mmol, yield 76%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.85 min, m / z 493.3 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ / ppm: 8.00 (1H, s), 7.97 (1H, d, J = 6.0Hz), 7.81-7.77 (2H, m), 7.65-7.62 (2H, m), 6.92-6.83 (3H, m), 6.32 (1H, d, J = 5.6Hz), 4.62-4.57 (1H, m), 4.46-4.40 (1H, m), 3.33-3.24 (2H, m), 3.16-3.11 (1H, m), 3.0 8 (2H, t, J = 8.0Hz), 2.72 (2H, t, J = 8.0Hz) .

[0272] Step 3: 5-[3-[3-[2-(trifluoromethyl)phenyl]-1H-pyrazole-5-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one Hydrazine hydrate (0.03 mL, 0.66 mmol) was added at room temperature to a stirred solution of 5-[3-[3-[2-(trifluoromethyl)phenyl]prop-2-inoyl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (163 mg, 0.3300 mmol) and t-BuOH (2 mL). The reaction mixture was heated at 85 °C for 1 hour, then poured into saturated NH4Cl aqueous solution (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain 5-[3-[3-[2-(trifluoromethyl)phenyl]-1H-pyrazole-5-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizin-2-one (112 mg, 0.22 mmol, yield 67%) as a white solid. UPLC-MS (ES+, final purity): 3.94 min, m / z 507.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ / ppm: 13.05 (0.6H, s), 13.00 (0.4H, s), 10.46 (1H, s), 7.95 (1H, d, J = 5.6Hz), 7.90-7.54 (4H , br m), 7.01-6.98 (1H, m), 6.95-6.86 (2H, m), 6.39-6.33 (1H, m), 6.28-6.23 (1H, m), 4. 50-4.41 (1H, m), 4.19-4.04 (1H, m), 3.52-3.42 (1H, m), 3.21-3.01 (2H, m), 2.93 (2H, t, J = 7.6Hz), 2.54 (2H, t, J = 7.6Hz).

[0273] The compounds shown in the table below were prepared in the same manner as in Example 23, using a suitable arylacetylene instead of 2-ethynyl-α,α,α-trifluorotoluene in Step 2. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4]

[0274] Example 24. Synthesis of 5-[3-[6-(trifluoromethyl)-1H-benzimidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 22) [ka] 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (246 mg, 0.65 mmol) is used with 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizine-4-yl) [I)oxychroman-3-carboxylic acid (200 mg, 0.59 mmol), 3,4-diaminobenzotrifluoride (114 mg, 0.65 mmol), DIPEA (0.31 mL, 1.76 mmol), and DMF (3 mL) were added to a stirred solution at room temperature under a nitrogen atmosphere and stirred for 1 hour. The solvent was removed by vacuum, and the residue was partitioned between water (50 mL) and DCM (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed by vacuum. Next, the residue was stirred in acetic acid (3 mL) at 80°C for 18 hours, after which the reaction mixture was cooled to room temperature and the solvent was removed by vacuum. The residue was partitioned between saturated NaHCO3 aqueous solution (100 mL) and DCM (100 mL), the organic layer was separated, dried over Na2SO4, filtered, and concentrated by vacuum. The residue was purified by column chromatography using a 0-5% MeOH / DCM eluent to obtain 5-[3-[6-(trifluoromethyl)-1H-benzimidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizine-2-one (75 mg, 0.16 mmol, yield 26%) as a white solid. UPLC-MS (ES+, final purity): 3.41 min, m / z 481.2 [M+ H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.92 (1H, br s), 10.48 (1H, s), 7.95 (1H, d, J = 9 .2Hz), 7.89-7.76 (1H, m), 7.76-7.70 (1H, m), 7.50 (1H, d, J = 8.8Hz), 7.06-7.03 (1H, m) , 6.93 (1H, dd, J = 9.2Hz, 2.8Hz), 6.89 (1H, d, 8.8Hz), 6.27 (1H, d, J = 6.0Hz), 4.65 (1H , m), 4.33 (1H, t, J = 9.2Hz), 3.71-3.62 (1H , m), 3.38-3.22 (2H, m), 2.93 (2H, t, J = 8.4Hz), 2.53 (2H, t, J = 8.4Hz, (partly under DMSO)).

[0275] The compounds listed in the table below were prepared in a similar manner, using a suitable diamine (either commercially available or synthetic) instead of 3,4-diaminobenzotrifluoride. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5]

[0276] Example 25. Synthesis of 5-[3-(3H-imidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 134) [ka] Step 1: N-(4-amino-3-pyridyl)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (307.2 mg, 0.81 mmol) was added under a nitrogen atmosphere to a stirred solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizine-4-yl)oxy]chroman-3-carboxylic acid (250 mg, 0.73 mmol), DIPEA (0.38 mL, 2.2 mmol), 3,4-diaminopyridine (88.2 mg, 0.81 mmol), and DMF (10 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum, and the residue was partitioned between water (20 mL) and DCM + a few drops of MeOH (20 mL). Subsequently, the aqueous phase was extracted with ELISA (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed under vacuum. Therefore, the crude product was purified by column chromatography using MeOH / DCM with a gradient of 0–5% as the eluent to obtain N-(4-amino-3-pyridyl)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizine-4-yl)oxy]chroman-3-carboxamide (195 mg, 0.45 mmol, yield 62%) as a yellow solid. UPLC-MS (ES +, low acidity): 1.13 min, m / z 432.2 [M+H] + .

[0277] Step 2: 5-[3-(3H-imidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one N-(4-amino-3-pyridyl)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizin-4-yl)oxy]chroman-3-carboxamide (144 mg, 0.33 mmol) in 1,4-dioxane (3 mL) was added to HCl (4 M in dioxane - 0.67 mL, 2.68 mmol) in a sealed vial. The reaction mixture was irradiated at 100°C for 2 hours, after which the solvent was removed under reduced pressure. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM + MeOH. The organic phase was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The crude product was purified by automated column chromatography using MeOH / DCM with a gradient of 0-12% as the eluent to obtain 5-[3-(3H-imidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (42.5 mg, 0.10 mmol, yield 31%) as a white solid. UPLC-MS (ES+, final purity): 2.30 min, m / z 414.2 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ / ppm: 13 .00-12.79 (1H, m), 10.47 (1H, s), 8.87 (1H, s), 8.28 (1H, d, J = 5.2Hz), 7.96 (1H, d, J = 5.6Hz), 7.61-7.50 (1H, m), 7.03 (1H, d, J = 2.4Hz), 6.95-6.87 (2H, m), 6.27 (1H, d, J = 5.6Hz), 4.64-4.58 (1H, m), 4.31 (1H, t, J = 10.0Hz), 3.70-3.60 (1H, m), 3.36-3.19 (2H, m, (partially underwater)), 2.93 (2H, t, J = 7.6Hz), 2.53 (2H, t, 8.0Hz, (partially under DMSO)).

[0278] Example 26. Synthesis of 5-[[2-(3-phenyl-1H-1,2,4-triazole-5-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-onehydrochloride (compound 44) [ka] Step 1: 2-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-ol 3,5-Dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (1.042 g, 3.35 mmol), 1,2,3,4-tetrahydroisoquinoline-7-ol (500 mg, 3.35 mmol), L-proline (38.6 mg, 0.34 mmol), copper(I) iodide (63.8 mg, 0.34 mmol), K2CO3 (1.39 g, 10.05 mmol), and DMF (3 mL) were combined in a sealed container and heated to 120°C for 18 hours. The reaction mixture was cooled to room temperature, the solvent was removed by vacuum, and the residue was partitioned between water (100 mL) and DCM (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-100% siRNA / petroleum ether eluent to obtain 2-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-ol (508 mg, 1.34 mmol, 40% yield) as a brown solid. UPLC-MS (ES+, low acidity): 1.64 min, m / z 379.1, 381.1 [M+H] + .

[0279] Step 2: 2-(5-phenyl-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-ol [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (173.6 mg, 0.21 mmol) was added to a stirred mixture of 2-(5-bromo-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-ol (806 mg, 2.13 mmol), phenylboronic acid (311 mg, 2.55 mmol), K2CO3 (881 mg, 6.38 mmol), 1,4-dioxane (9 mL), and water (1 mL) under an inert atmosphere at room temperature. The reaction mixture was heated to 80°C for 3 hours, then cooled to room temperature and the solvent was removed by vacuum. The residue was suspended in DCM (10 mL), filtered through Celite, and then removed from DCM ( The solution was washed with 10 mL of solution. The residue was vacuum concentrated and purified by column chromatography using a 0-100% siRNA / petroleum ether eluent to obtain 2-(5-phenyl-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-ol (510 mg, 1.35 mmol, yield 64%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.85 min, m / z 399.3 [M+Na] + , 293.2 [M-THP] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 9.23 (1H, s), 7.98-7.93 (2H, m), 7.48-7.37 (3H, m), 6.98 (1H, d, 8. 4Hz), 6.61 (1H, dd, J = 8.4Hz, 2.8Hz), 6.57 (1H, d, J = 2.8Hz), 5.31 (1H, dd, J = 10.0Hz, 2.0Hz), 4.50-4.46 (1H, m), 4.35-4.31 (1H, m), 4.10-4.03 (1H, m), 3.72-3.64 (2H, m), 3 .45-3.35 (1H, m), 3.10-3.01 (1H, m), 2.85-2.76 (1H, m), 2.06-1.95 (2H, m), 1.90-1.53 ​​( 4H, m).

[0280] Step 3: 5-[[2-(5-phenyl-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one 2-(5-phenyl-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-ol (510 mg, 1.35 mmol), 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (225.1 mg, 1.35 mmol), K2CO3 (936 mg, 6.77 mmol), and DMSO (10 mL) were combined in a sealed vial and stirred at 110°C for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-100% siRNA / petroleum ether eluent to obtain 5-[[2-(5-phenyl-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizin-2-one (192 mg, 0.37 mmol, yield 27%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.92 min, m / z 523.3 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ / ppm: 10.56 (1H, s), 8.00-7.93 (2H, m), 7.4 8-7.39 (3H, m), 7.31-7.28 (1H, m), 7.03 (1H , d, J = 2.8Hz), 6.99 (1H, dd, J = 8.4Hz, 2.8 Hz), 6.34 (1H, d, = 5.6Hz), 5.34 (1H, dd, J = 10.0Hz, 2.4Hz), 4.56 (1H, d, J = 16.0Hz), 4 .44 (1H, d, J = 16.0Hz), 4.08-4.00 (1H, m), 3.81-3.65 (2H, m), 3.50-3.42 (1H, m), 3.25-3.14 (1H, m), 3.00-2.88 (3H, m), 2.55-2.50 (3H, m), 1.90-1.54 (6H, m).

[0281] Step 4 5-[[2-(3-phenyl-1H-1,2,4-triazole-5-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizine-2-onehydrochloride HCl (4M in 1,4-dioxane - 0.37 mL, 1.47 mmol) was added to 5-[[2-(5-phenyl-2-tetrahydropyran-2-yl-1,2,4-triazole-3-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizin-2-one (192 mg, 0.37 mmol) in DCM (10 mL) under a nitrogen atmosphere at room temperature, and the reaction was stirred for 18 hours. The solvent was removed by vacuum, and column chromatography was performed using a 0-10% MeOH / DCM eluent. The residue was then purified to obtain 5-[[2-(3-phenyl-1H-1,2,4-triazole-5-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizine-2-onehydrochloride (50 mg, 0.11 mmol, yield 29%) as a yellow solid. UPLC-MS (ES+, final purity) ): 3.39 minutes, m / z 439.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ / ppm: 10.63 (1H, s), 8.04-7.95 (3H, m), 7.52-7.44 (3H, m), 7.30 (1H, d, J = 7.6Hz), 7.05-6.99 (2H, m), 6.39 (1H, d, J = 6. 0Hz), 4.72-4.67 (2H, m), 3.83-3.77 (2H, m), The broad peaks at 2.99–2.91 (3H, m) and 2.59–2.54 (3H, m) and 5.4 ppm likely contain one interchangeable HCl salt.

[0282] Example 27. Synthesis of 7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]-N-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (compound 46) [ka] Step 1: Benzyl 7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate Benzyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (500 mg, 1.76 mmol), 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (0.29 g, 1.76 mmol), and K2CO3 (0.91 g, 6.55 mmol) were suspended in DMSO (50 mL) and heated to 110°C for 18 hours. The reaction mixture was cooled to room temperature and gradually added to an aqueous solution of citric acid (1.36 g, 7.06 mmol in 50 mL of H2O) (which caused foaming), and stirred for 1 hour. Water (200 mL) was added, and the resulting mixture was extracted with DCM (2 × 100 mL). The combined organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using a 0-75% siRNA / petroleum ether eluent to obtain benzyl 7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (510 mg, 1.19 mmol, yield 67%) as a white solid. UPLC-MS (ES+, low acidity): 1.69 min, m / z 430.3 [M+H] + . 1 H NM R (400MHz, DMSO-d6) δ / ppm: 10.50 (1H, s), 7 .97 (1H, d, J = 5.6Hz), 7.41-7.35 (5H, m), 7 .25 (1H, d, J = 8.4Hz), 7.03 (1H, d, J = 6.8H z), 6.96 (1H, dd, J = 8.0Hz, 2.4Hz), 6.31 (1 H, d, J = 5.5Hz), 5.13 (2H, s), 4.66-4.55 (2 H, m), 3.70-3.62 (2H, m), 2.90 (2H, t, J = 7.2Hz), 2.82 (2H, J = 5.6Hz), 2.55-2.53 (2H, m (partially under DMSO).

[0283] Step 2: 5-(1,2,3,4-tetrahydroisoquinoline-7-yloxy)-3,4-dihydro-1H-1,8-naphthyrizine-2-one Palladium (10 wt.% on carbon powder, dry (50 mg)) was added to a stirred solution of benzyl 7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (510 mg, 1.19 mmol) in siRNA (20 mL) and MeOH (5 mL) at room temperature under a nitrogen atmosphere. An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 24 hours. The crude product was filtered through Celite, washed with MeOH (10 mL), and the filtrate was concentrated under vacuum to obtain 5-(1,2,3,4-tetrahydroisoquinoline-7-yloxy)-3,4-dihydro-1H-1,8-naphthirizine-2-one (222 mg, 0.75 mmol, yield 63%) as a yellow solid. The product was used in the next step without further purification. UPLC-MS (ES+, low acidity) degree): 0.91 min, m / z 296.2 [M+H] + . 1 1H NMR (400MHz) , CDCl3) δ / ppm: 8.17 (1H, s), 7.99 (1H, d, J = 6.0Hz), 7.15 (1H, d, J = 8.4Hz), 6.86 (1H, dd, J = 8.4Hz, 2.8Hz), 6.76 (1H, d, J = 2.8Hz), 6.34 (1H, d, J = 6.0Hz), 4.03 (2H, s), 3.18 (2H, t, J = 6.0Hz), 3.08 (2H, t, J = 8.0Hz) , 2.83 (2H, t, J = 6.0Hz), 2.72 (2H, t, J = 8.0Hz). No interchangeable protons were observed.

[0284] Step 3 7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]-N-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxamide Phenyl isocyanate (0.02 mL, 0.19 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 5-(1,2,3,4-tetrahydroisoquinoline-7-yloxy)-3,4-dihydro-1H-1,8-naphthyrizin-2-one (50 mg, 0.17 mmol) and DIPEA (0.06 mL, 0.34 mmol) in DCM (5 mL). The reaction mixture was stirred for 1 hour, and then diluted with water (20 mL) and DCM (15 mL). The organic layer was separated and passed through a phase separator, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-100% siRNA / petroleum ether eluent to obtain 7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]-N-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (29 mg, 0.07 mmol, yield 41%) as a white solid. UPLC-MS (ES+, most Final purity): 3.35 min, m / z 415.3 [M+H] + . 1 1H NMR (400M Hz, DMSO-d6) δ / ppm: 10.51 (1H, s), 8.58 (1H , s), 7.98 (1H, d, J = 5.6Hz), 7.50-7.46 (2H , m), 7.30-7.22 (3H, m), 7.00-6.92 (3H, m), 6.34 (1H, d, J = 5.6Hz), 4.64 (2H, s), 3.73 (2H, t, J = 6.0Hz), 2.94-2.85 (4H, m), 2.55-2.53 (2H, m, (partially below DMSO peak)).

[0285] Use an appropriate aryl isocyanate instead of phenyl isocyanate in Step 3. Then, the compounds listed in the table below were prepared using the same method. [Table 19-1] [Table 19-2]

[0286] Example 28. Synthesis of 5-[[2-(1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 159) [ka] Step 1: 2-(1H-benzimidazole-2-yl)-7-benzyloxy-3,4-dihydro-1H-isoquinoline 7-Benzyloxy-1,2,3,4-tetrahydroisoquinoline (158 mg, 0.66 mmol), 2-chlorobenzimidazole (101 mg, 0.66 mmol), and 1,4-dioxane (1.2 mL) were mixed in a sealed vial and irradiated at 180°C for 1 hour. The residue was dissolved in DCM, washed with saturated NaHCO3 aqueous solution, and then dried in a phase separator. The solvent was removed by vacuum, and the residue was purified by column chromatography using a 0-50% siRNA / petroleum ether gradient as the eluent to obtain 2-(1H-benzimidazole-2-yl)-7-benzyloxy-3,4-dihydro-1H-isoquinoline (175 mg, 0.49 mmol, yield 75%) as a white solid. UPLC-MS ( ES+, low acidity): 1.50 min, m / z 356.5 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ / ppm: 11.45 (1H, s), 7.49-7.27 (5H, m), 7.20 (2H, dd, J = 14.1Hz, 7. 6Hz), 7.09 (1H, d, J = 8.3Hz), 6.99-6.81 (4H, m), 5.10 (2H, s), 4.68 (2H, s), 3.78 (2H, t, J = 5.9Hz), 2.84 (2H, t, J = 5.9Hz).

[0287] Step 2: 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane

[0288] Sodium hydride (60% dispersed in mineral oil - 38.3 mg, 0.96 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 2-(1H-benzimidazole-2-yl)-7-benzyloxy-3,4-dihydro-1H-isoquinoline (170 mg, 0.48 mmol) and DMF (100 mL). After 20 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (0.13 mL, 0.72 mmol) was added, and the mixture was stirred for 18 hours. The reaction product was quenched with water (1 mL), and the solvent was removed by vacuum. Water (20 mL) was added, followed by extraction with DCM (2 × 20 mL). The combined organic layer was dried over Na₂SO₄, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-40% siRNA / petroleum ether gradient as the eluent to obtain 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 0.41 mmol, yield 86%) as a colorless rubber. UPLC-MS (ES+, low acidity): 1.93 min. m / z 486.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 7.64-7.55 (1H, m), 7.45-7.28 (6H, m), 7.24-7.15 (2H, m), 7.10 (1H, d, J = 8.4Hz), 6.85 (1H, dd, J = 8.4Hz, 2.7Hz), 6.76 (1H, d , J = 2.6 Hz), 5.34 (2H, s), 5.05 (2H, s), 4. 60 (2H, s), 3.78-3.66 (4H, m), 3.02 (2H, t, J = 5.9 Hz), 1.01-0.96 (2H, m), 0.00 (9H, s) .

[0289] Step 3: 2-[1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (195 mg, 0.40 mmol) was dissolved in MeOH (4 mL), and Pd(OH)2 (56 mg, 0.40 mmol) was added under an inert atmosphere. An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed, followed by stirring overnight under an H2 atmosphere. The crude product was filtered through Celite, flushed with MeOH, and the filtrate was concentrated under vacuum. The residue was analyzed by column chromatography using a 0-50% siRNA / petroleum ether gradient as the eluent. The compound was purified to obtain 2-[1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol (120 mg, 0.30 mmol, yield 76%) as a colorless rubber, which crystallized upon standing. UPLC-MS (ES+, low acidity): 1.58 min, m / z 396.6 [M+H] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 8.45 (1H, s), 7.61-7.55 (1H, m), 7.33-7.28 (1H, m), 7.2 1-7.14 (2H, m), 6.93 (1H, d, J = 8.3Hz), 6.6 8 (1H, dd, J = 8.3Hz, 2.6Hz), 6.63 (1H, d, J = 2.5Hz), 5.35 (2H, s), 4.57 (2H, s), 3.81-3.69 (4H, m), 2.92 (2H, t, J = 5.8 Hz), 1.03-0.96 (2H, m), 0.00 (9H, s).

[0290] Step 4 5-[[2-[1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one Potassium tert-butoxide (37.4 mg, 0.33 mmol) was added to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (50.4 mg, 0.30 mmol) and 2-[1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol (120 mg, 0.30 mmol) in DMF (2 mL), and the reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum. The residue was partitioned between  and water; the organic matter was washed with saturated brine, dried in a phase separator, and the solvent was removed by vacuum. The residue was purified by column chromatography eluting with 25-100% siRNA / petroleum ether to obtain 5-[[2-[1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one (94 mg, 0.17 mmol, yield 57%) as a colorless rubber. UPLC-MS (ES+, low acidity): 1.65 min, m / z 542.5 [M+H] + . 1 H NMR (400MHz, CDCl3) δ / ppm: 8.69 (1H, s), 8.01 (1H, d, J = 5.9Hz) , 7.63-7.58 (1H, m), 7.34-7.30 (1H, m), 7.2 5-7.16 (3H, m), 6.93-6.85 (2H, m), 6.35 (1H , d, J = 5.9Hz), 5.36 (2H, s), 4.65 (2H, s), 3.82-3.72 (4H, m), 3.13-3.02 (4H, m), 2.70 (2H, dd, J = 8.4Hz, 7.0 Hz), 1.03-0.96 (2H, m), 0.00 (9H, s).

[0291] Step 5 5-[[2-(1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one Trifluoroacetic acid (0.64 mL, 8.31 mmol) was added to a stirred solution of 5-[[2-[1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthirizine-2-one (90 mg, 0.17 mmol) in DCM (2 mL) in a sealed vial. The mixture was heated to 40°C for 18 hours, after which the solvent was removed by vacuum. The residue was loaded onto an SCX-2 column and flushed first with MeOH (2 × 10 mL), then with NH3 in MeOH (10 mL) to elute the product. The residue was then purified by column chromatography using MeOH / DCM with a gradient of 1–8% as the eluent to obtain a colorless rubber, which was pulverized in MeCN / Et2O to obtain a white solid. The solid is filtered, washed with Et2O, and dried to obtain 5-[[2-(1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro -1H-1,8-naphthirizine-2-one (29 mg, 0.070 mmol, 42% yield) as a white solid. UPLC-MS (ES+, final purity): 2.52 min, m / z 412.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ / pp m: 12.21 (1H, s), 10.52 (1H, s), 7.99 (1H, d , J = 5.8 Hz), 7.33-7.25 3H, m), 7.07-6.97 ( 4H, m), 6.35 (1H, d, J = 5.8 Hz), 4.76 (2H, s ), 3.85 (2H, t, J = 5.9 Hz), 2.98 (2H, t, J = 5.9Hz), 2.92 (2H, t, J = 7.9Hz), 2.57-2.52 (2H, t, J = 7.9Hz, (partly under DMSO)).

[0292] The compounds listed in the table below were prepared in a similar manner, using a suitable heteroaryl chloride instead of 2-chlorobenzimidazole in Step 1. [Table 20]

[0293] Example 29. Synthesis of 5-[[2-(5-phenyl-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 162) [ka] Step 1: 5-bromo-1,3-dihydrobenzimidazole-2-one 1,1'-Carbonyldiimidazole (1.73 g, 10.69 mmol) was added to a stirred solution of 4-bromo-1,2-diaminobenzene (1 g, 5.35 mmol) in DMF (10 mL) under a nitrogen atmosphere at 25°C, and the reaction mixture was stirred for 18 hours. The solvent was reduced under vacuum, the residue was diluted with water and siRNA, and the solid was crushed. The solid was filtered, slurryed in water, sonicated, filtered again, washed with water, and dried to obtain 5-bromo-1,3-dihydrobenzimidazole-2-one (912 mg, 4.28 mmol, yield 80%) as a brown solid. UPLC-MS (ES+, low acidity): 1.28 min, m / z 212.9, 214.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 10.79-10.73 (2H, m), 7.08 (1H, dd, J = 8.2Hz, 2.0Hz), 7.05 (1H, d, J = 1.9H z), 6.87 (1H, d, J = 8.2Hz).

[0294] Step 2: 6-bromo-2-chloro-1H-benzimidazole 5-Bromo-1,3-dihydrobenzimidazole-2-one (912 mg, 4.28 mmol) was dissolved in POCl3 (7.98 mL, 85.62 mmol), and the reaction mixture was heated at 95°C for 4 hours. The reaction mixture was then reduced under vacuum, and the residue was azeotropically reacted with toluene. The residue was quenched with saturated NaHCO3 solution, the solid was pulverized, sonicated, filtered, washed with water, and dried to obtain 6-bromo-2-chloro-1H-benzimidazole (855 mg, 3.69 mmol, yield 86%) as a light brown solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity) : 1.44 minutes, m / z 230.8, 232.8, 234.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 7.74 (1H, d, J = 1.9Hz), 7.49 (1H, d, J = 8.6Hz), 7.38 (1H, dd, J = 8.6Hz, 2.0Hz). Exchangeable protons disappear.

[0295] Step 3: 7-Benzyloxy-2-(5-bromo-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline Eight separate microwave vials, each containing 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 mg, 0.18 mmol), 6-bromo-2-chloro-1H-benzimidazole (46 mg, 0.2 mmol), and 1,4-dioxane (2.5 mL), were sealed and heated in a microwave oven to 180°C for 60 minutes. A solid precipitate formed in each vial. All reaction mixtures were filtered, and the combined solid was further washed with dioxane and dried to obtain 7-benzyloxy-2-(5-bromo-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline (626 mg, 1.4 mmol, 99% yield) as a green / brown solid. UPLC-MS (ES+, low acidity) degree): 1.59 min, m / z 434.1;436.0 [M+H]+ (67%)

[0296] Step 4 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-bromo-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane Sodium hydride (60% dispersed in mineral oil - 168.9 mg, 4.22 mmol) was added at room temperature under a nitrogen atmosphere to a stirred solution of 7-benzyloxy-2-(5-bromo-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline (692 mg, 1.12 mmol) and DMF (10 mL). After 20 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (0.3 mL, 1.67 mmol) was added, and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with water (1 mL), and the solvent was removed by vacuum. Next, the residue was partitioned between water (20 mL) and siRNA (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using a 0-40% siRNA / petroleum ether eluent to obtain 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-bromo-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (442 mg, 0.78 mmol, yield 70%) as a pale yellow rubber. UPLC-MS (ES+, low acidity): 2.27 and 2.29 mins, m / z 564.3, 566.2 [M+H] + The presence of two SEM isomers.

[0297] Step 5 (Method A) 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-phenyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane Potassium carbonate (151.3 mg, 1.09 mmol), 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-bromo-benzimidazole-1-yl]methoxy]ethyl-trimethylsilane (206 mg, 0.36 mmol), phenylboronic acid (48.9 mg, 0.40 mmol), 1,4-dioxane (4 mL), and water (1 mL) were combined and stirred at room temperature under a nitrogen atmosphere. Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (29.8 mg, 0.04 mmol) was added. The reaction mixture was heated at 90°C for 18 hours, then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 0-35% siRNA / petroleum ether eluent to obtain 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-phenyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 0.27 mmol, yield 73%) as a pale yellow oil. UPLC-MS (ES+, low acidity): 2.11 min, m / z 562.8 [M+H]+.

[0298] Step 6 2-[5-phenyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol Dissolve 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-phenyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 0.27 mmol) in MeOH (4 mL) and hydroxylate parahydroxymethyl silane. Dium (3.04 mg, 0.02 mmol) was added under a nitrogen atmosphere. An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed. The mixture was then stirred overnight under an H2 atmosphere. The crude product was filtered through Celite, washed with MeOH, and the solvent was removed under vacuum to obtain 2-[5-phenyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol (117 mg, 0.25 mmol, yield 93%) as a colorless rubber. UPLC-MS (ES+, low acidity) :1.81min, m / z 472.6 [M+H] + .

[0299] Step 7 5-[[2-[5-phenyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-onol Potassium tert-butoxide (83.5 mg, 0.74 mmol) was added to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (41.2 mg, 0.25 mmol) in DMF (2 mL) in a resealable vial. The vial was sealed and heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was reduced under vacuum. The crude product was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated brine, dried in a phase separator, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 25-100% siRNA / petroleum ether gradient as the eluent to obtain 5-[[2-[5-phenyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizin-2-one (90 mg, 0.15 mmol, yield 59%) as a colorless, rubbery substance. UPLC-MS (ES+, low acidity) : 1.87 minutes, m / z 618.5 [M+H] + .

[0300] Step 8 5-[[2-(5-phenyl-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one Trifluoroacetic acid (0.56 mL, 7.29 mmol) was added to a stirred solution of 5-[[2-[5-phenyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizin-2-one (90 mg, 0.15 mmol) in DCM (2 mL) in a sealable vial. The vial was sealed and heated to 40°C for 18 hours. The reaction mixture was reduced under vacuum and loaded onto an SCX-2 column, which was flushed with methanol (2×), then NH3 in MeOH, and then 20% DCM in MeOH / NH3 to elute the product. The crude product was purified by column chromatography using MeOH / DCM with a gradient of 1-8% as the eluent to obtain a colorless rubber, which was then pulverized in MeCN / Et2O to obtain a white solid. The solid was filtered, washed with Et2O, and subsequently sonicated in MeOH to precipitate the white solid. The entire suspension was evaporated and dried to obtain 5-[[2-(5-phenyl-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthirizine-2-one (27 mg, 0.053 mmol, yield 36%) as an off-white solid. UPLC-MS (ES+, final purity): 3.04 min. m / z 488.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 11.57 (1H, s), 10.51 (1H, s), 7.99 (1H, dd, J = 5.7Hz, 0.7Hz), 7.66-7.59 (2H, m), 7.52-7.38 (3H, m), 7.33-7.18 (3H, m), 7.05 (1H, d, J = 2.5Hz), 6.98 (1H, dd, J = 8.3Hz, 2.6Hz), 6.35 (1H, d, J = 5.8Hz), 4.76 (2H, s ), 3.85 (2H, t, J = 5.9Hz), 3.00-2.89 (4H, m ), 2.58-2.52 (3H, m, (partially under DMSO)).

[0301] Alternatively, step 5 could have been performed using method B.

[0302] 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-bromo-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (255 mg, 0.45 mmol), tripotassium phosphate tribasic (0.29 g, 1.35 mmol), and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150.5 mg, 0.68 mmol) were suspended in toluene (2 mL) and water (1 mL), and degassed under a nitrogen atmosphere in a sealable vial. Next, tricyclohexylphosphine (0.03 g, 0.09 mmol) and palladium(II) acetate (0.01 g, 0.03 mmol) were added, followed by further degassing, sealing of the vial, and heating at 90°C for 18 hours. The reaction mixture was cooled and water was removed. The organic matter was reduced under vacuum on silica, and the product was purified by silica column chromatography using siRNA / petroleum ether with a gradient of 0-80% as the eluent to obtain 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-(2,5-dimethylpyrazole-3-yl)benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (110 mg, 0.19 mmol, yield 42%) as a colorless rubber. UPLC-MS (ES+, low acidity): 2.02 and 2.05 min, m / z 580.5 [M+H] + (2 SEM-protected isomers).

[0303] The compounds listed in the table below were prepared using a similar method, employing appropriate boronic acids / esters and applying appropriate techniques. [Table 21]

[0304] Example 30. Synthesis of 5-[[2-(5-propyl-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 161) [ka] Step 1: 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-cyclopropyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-bromo-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (205 mg, 0.36 mmol), cyclopropylboronic acid (0.08 g, 0.91 mmol), and tripotassium tribasic phosphate (0.23 g, 1.09 mmol) were suspended in toluene (2 mL) and water (1 mL) at room temperature and degassed in a resealable vial under a nitrogen atmosphere. Next, tricyclohexylphosphine (0.02 g, 0.07 mmol) and palladium(II) acetate (0.01 g, 0.03 mmol) were added, the vial was sealed, and heated at 100 °C for 2 hours. The reaction mixture was cooled and the water was removed. The organic matter was reduced under vacuum on silica, and the product was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-35% as the eluent to obtain 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-cyclopropyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (155 mg, 0.29 mmol, yield 81%) as a colorless rubber. UPLC-MS (ES+, low acidity) ): 1.98 min, m / z 526.9 [M+H] + .

[0305] Step 2: 2-[5-propyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol 2-[[2-(7-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl)-5-cyclopropyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (155 mg, 0.29 mmol) was dissolved in methanol (4 mL), and palladium hydroxide (3.36 mg, 0.02 mmol) was added under a nitrogen atmosphere. An H2 balloon was attached to the reaction, and three vacuum / H2 cycles were performed. Then, the mixture was stirred overnight under an H2 atmosphere. The crude product was filtered through Celite, washed with MeOH, and the solvent was removed under vacuum to obtain 2-[5-propyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-ol (107 mg, 0.24 mmol, yield 83%) as a colorless rubber. UPLC-MS (ES+, low acidity): 1.78 min, m / z 438.6 [M+H] + .

[0306] Step 3: 5-[[2-[5-propyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one Potassium tert-butoxide (83.5 mg, 0.74 mmol) is mixed with 5-fluoro-3,4-dihydro-1H-1,8-naphthyridine-2-one (40.6 mg, 0.24 mmol) and 2-[5-propyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-di in a resealable vial of DMF (2 mL). The reaction mixture was added to a stirred solution of hydro-1H-isoquinoline-7-ol (107 mg, 0.24 mmol), sealed, and heated at 100°C for 72 hours. The reaction mixture was cooled to room temperature, and the solvent was reduced under vacuum. The crude product was partitioned between siRNA and water. The organic layer was separated, washed with saturated brine, dried in a phase separator, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 25-100%, yielding 5-[[2-[5-propyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one (41 mg, 0.07 mmol, yield 29%) as a colorless rubber. UPLC-MS (ES+, low acidity): 1.81 min, m / z 584.5 [M+H] + .

[0307] Step 3: 5-[[2-(5-propyl-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridine-2-one Trifluoroacetic acid (0.27 mL, 3.51 mmol) was added to a stirred solution of 5-[[2-[5-propyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizin-2-one (41 mg, 0.07 mmol) in DCM (2 mL) in a sealable vial. The reaction mixture was sealed and heated at 40°C for 18 hours. The reaction mixture was reduced under vacuum and loaded into an SCX cartridge. The product was eluted by flushing first with MeOH, then with MeOH / NH3, and then with 20% DCM:MeOH / NH3. The product was then purified by silica column chromatography using MeOH / DCM with a gradient of 1–8% as the eluent to obtain colorless rubber. The compound was re-purified using reversed-phase column chromatography with a gradient of 0-30% (acetonitrile + 0.1% formic acid) / (water + 0.1% formic acid) as the eluent. The fraction containing the product was re-purified using preparative LC-MS (initial method). The fraction containing the compound was loaded onto an SCX column and flushed first with MeOH, then with MeOH / NH3, to elute the product and obtain 5-[[2-(5-propyl-1H-benzimidazole-2-yl)-3,4-dihydro-1H-isoquinoline-7-yl]oxy]-3,4-dihydro-1H-1,8-naphthyrizin-2-one (8 mg, 0.018 mmol, yield 25%) as an off-white solid. UPLC-MS (ES+, final purity): 3.03 min, m / z 454.3 [M+H] + . 1 1H NMR (400MHz, DMS) O-d6) δ / ppm: 11.80 (1H, s), 10.50 (1H, s), 7.98 (1H, d, J = 5.8Hz), 7.27 (1H, d, J = 8.3H z), 7.13 (1H, d, J = 8.0Hz), 7.07-6.94 (3H, m), 6.81 (1H, dd, J = 8.0Hz, 1.6Hz), 6.34 (1 H, d, J = 5.8Hz), 4.72 (2H, s), 3.81 (2H, t, J = 5.9 Hz), 2.98-2.87 (4H, m), 2.62-2.51 (4H, m), 1.65-1.51 (2H, m), 0.88 (3H, t, J = 7.3Hz).

[0308] Example 31. Synthesis of N-[4-[3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide (compound 155) [ka] Step 1: 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-N-[2-(4-fluorophenyl)-2-oxo-ethyl]chroman-3-carboxamide To a solution of 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]chroman-3-carboxylic acid (65 mg, 0.18 mmol) and 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (54.7 mg, 0.20 mmol) in THF (1.8 mL), T3P (164 μL, 0.28 mmol) and DIPEA (99 μL, 0.57 mmol) were added, and the mixture was heated at 65°C for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in SiO (25 mL). The organic layer was washed with water (2 × 10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and the solvent was removed under vacuum to obtain 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-N-[2-(4-fluorophenyl)-2-oxo-ethyl]chroman-3-carboxamide (86 mg, 0.17 mmol, yield 95%) as a yellow solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity) ): 1.46 min, m / z 490.6 [M+H] + .

[0309] Step 2 N-[4-[3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide A suspension of 6-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-N-[2-(4-fluorophenyl)-2-oxo-ethyl]chroman-3-carboxamide (85.5 mg, 0.17 mmol) in n-BuOH (1 mL) was mixed with NH4OAc (134.6 mg, 1.75 mmol) and Et3N (26 μL, 0.18 mmol), and the mixture was irradiated at 150 °C for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in ELISA (25 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (10 mL), water (2 × 10 mL), and brine (10 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by flash chromatography using MeOH / DCM with a gradient of 0-10% as the eluent, followed by purification by preparative LC-MS. The fraction containing the product was dried and loaded onto an SCX-2 column. The column was flushed first with MeOH (10 mL) and then with NH3 in MeOH (10 mL) to elute the product. The filtrate was concentrated to obtain N-[4-[3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide (10 mg, 0.022 mmol, 13% yield) as a white solid. UPLC-MS (ES+, final purity): 2.73 min, m / z 471.3 [ M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6) δ / ppm: 12.33 and 12.10 (0.2 and 0.8H, 2 s, mixture of tautomers), 10.80 (1H, s), 8.16 (1H, d, J = 5.7Hz), 7.80-7.42 (2H, m), 7.65 (1H, d, J = 2.5Hz), 7.57 (1H, br s), 7.25-7.10 (2H, m), 7.02 (1H, d, J = 2.5Hz), 6.94-6.86 (2H, m*), 6.62 (1H, dd, J = 5 .7Hz, 2.4Hz), 4.54-4.48 (1H, m), 4.16-4.08 (1H, m), 3.44-3.34 (1H, m), 3.28-3.18 (1H, m), 3.15-3.07 (1H, m), 1.97 (1H, quint, J = 6.2Hz), 0.77 (4H, d, J = 6.2Hz).

[0310] Example 32. Synthesis of 4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-N-(2-pyridyl)pyridine-2-amine (compound 140) [ka] Step 1: 6-[(2-chloro-4-pyridyl)oxy]-N-phenacyl-chroman-3-carboxamide To a solution of 6-[(2-chloro-4-pyridyl)oxy]chroman-3-carboxylic acid (437 mg, 1.43 mmol) and 2-aminoacetophenone hydrochloride (270 mg, 1.57 mmol) in THF (14 mL), T3P (1.28 mL, 2.14 mmol) and DIPEA (0.8 mL, 4.58 mmol) were added, and the mixture was heated at 65°C for 1.5 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in SiO (60 mL). The organic layer was washed with water (2 × 20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, and the solvent was removed under vacuum to obtain 6-[(2-chloro-4-pyridyl)oxy]-N-phenacyl-chroman-3-carboxamide (604.5 mg, 1.43 mmol, yield 100%) as a pale brown solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.72 min, m / z 423.3 [M+H] + .

[0311] Step 2: 2-Chloro-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine To a suspension of 6-[(2-chloro-4-pyridyl)oxy]-N-phenacyl-chroman-3-carboxamide (513 mg, 1.21 mmol) in n-BuOH (10 mL), NH4OAc (935.2 mg, 12.13 mmol) and Et3N (169 μL, 1.21 mmol) were added. The vial was sealed and the mixture was irradiated at 150 °C for 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in SiO2 (60 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (20 mL), water (2 × 20 mL), and brine (20 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum. Column chromatography using SiO2 / petroleum ether with a gradient of 0 to 100% was performed. The residue was purified to obtain 2-chloro-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine (314.9 mg, 0.78 mmol, yield 64%) as a light brown solid. UPLC-MS (ES+, low acidity): 1.43 min, m / z 404.3 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) ) δ / ppm: 8.27 (1H, dd, J = 5.6, 0.3Hz), 7.77 -7.73 (2H, m), 7.69 (1H, br s), 7.43-7.36 (2H, m), 7.28-7.22 (1H, m), 7.10 (1H, d, J = 2.8Hz), 7.00 (1H, dd, J = 8.8, 2.8Hz), 6.96-6.92 (3H, m), 4.57-4.51 (1H, m), 4.25-4.18 (1 H, m), 3.53 (1H, br s), 3.32-3.25 (2H, m), 3 .18 (1H, dd, J = 16.6, 5.3Hz), 0.89-0.79 (1H, m).

[0312] Step 3: 4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-N-(2-pyridyl)pyridine-2-amine A tert-butanol (0.6 mL) solution containing 2-chloro-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine (50 mg, 0.12 mmol), 2-aminopyridine (17.5 mg, 0.19 mmol), XPhos Pd G2 (9.8 mg, 0.01 mmol), XPhos (5.9 mg, 0.01 mmol), and K2CO3 (51.3 mg, 0.3700 mmol) was irradiated at 130°C for 1 hour under a nitrogen atmosphere. After this time, additional 2-aminopyridine (17.5 mg, 0.1900 mmol), K2CO3 (51.3 mg, 0.37 mmol), XPhos Pd G2 (9.8 mg, 0.01 mmol) and XPhos (5.9 mg, 0.01 mmol) were added, and the mixture was irradiated at 160°C for 1 hour. The mixture was then passed through a Celite plug, and the filtered solid was washed with siRNA. The filtrate was concentrated, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-10% as the eluent, followed by purification by preparative LC-MS. The fraction containing the product was dried and loaded onto an SCX-2 column, which was flushed first with MeOH (10 mL) and then with NH3 in MeOH (10 mL) to elute the product. The filtrate was concentrated to obtain 4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-N-(2-pyridyl)pyridine-2-amine (11.5 mg, 0.025 mmol, 20% yield) as a white solid. UPLC-MS (ES+, final purity): 2.47 min, m / z 462.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12 .37 (1H, br s), 9.66 (1H, br s), 8.17-8.14 ( 1H, m), 8.08 (1H, d, J = 5.8Hz), 7.76-7.70 ( 2H, m), 7.69-7.60 (2H, m), 7.55 (1H, br s), 7.40-7.31 (3H, m), 7.21-7.15 (1H, m), 7.04 (1H, d, J = 2.7Hz), 6.94 (1H, dd, J = 8.8Hz, 2.7Hz), 6.90 (1H, d, J = 8.8Hz), 6.87-6.82 (1H, m), 6.41 (1H, dd, J = 5.8Hz, 2.1Hz), 4.5 6-4.49 (1H, m), 4.17-4.10 (1H, m), 3.45-3.36 (1H, m), 3.26 (1H, dd, J = 16.7Hz, 10.6Hz) , 3.18-3.09 (1H, m).

[0313] In Step 3, the compounds listed in the table below were prepared using the appropriate amine in a similar manner. [Table 22]

[0314] Example 33. Synthesis of 2,2-difluoro-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide (compound 137) [ka] Step 1: 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-4-phenylimidazole-1-yl]methoxy]ethyl-trimethyl-silane and -2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-5-phenylimidazole-1-yl]methoxy]ethyl-trimethyl-silane Under a nitrogen atmosphere, 2-chloro-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine (553 mg, 1.37 mmol) was added to a solution of 2-chloro-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine (13.7 mL) in anhydrous THF (60% - 82.1 mg, 2.05 mmol) in mineral oil at 0°C. The mixture was stirred at 0°C for 45 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (300 μL, 1.7 mmol) was added dropwise, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (15 mL) and extracted with RINKAN (3 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-50% as the eluent to obtain 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-4-phenyl-imidazole-1-yl]methoxy]ethyl-trimethyl-silane (444 mg, 0.83 mmol, yield 61%) and 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-5-phenyl-imidazole-1-yl]methoxy]ethyl-trimethyl-silane (120.4 mg, 0.23 mmol, yield 16%), both as yellow rubber.

[0315] 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-4-phenylimidazole-1-yl]methoxy]ethyl-trimethyl-silane: U PLC-MS (ES+, low acidity): 2.23 min, m / z 535.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 8.29-8.26 (1H, m), 7.77 (1H, s), 7.76-7.72 (2H, m), 7 .37-7.32 (2H, m), 7.22-7.16 (1H, m), 7.08 ( 1H, d, J = 2.8Hz), 7.00 (1H, dd, J = 8.8Hz, 2 .8Hz), 6.97-6.92 (3H, m), 5.48 (1H, d, J = 1 1.1Hz), 5.42 (1H, d, J = 11.1Hz), 4.50-4.44 (1H, m), 4.11-4.04 (1H, m), 3.61-3.52 (3H, m), 3.32-3.25 (1H, m), 3.08-2.99 (1H, m), 0 .93-0.86 (2H, m), -0.02 (9H, s).

[0316] 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-5-phenylimidazole-1-yl]methoxy]ethyl-trimethyl-silane: U PLC-MS (ES+, low acidity): 2.00 min, m / z 535.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 8.29-8.26 (1H, m), 7.51-7.38 (5H, m), 7.07 (1H, d, J = 2.8Hz), 7.02 (1H, s), 7.00 (1H, dd, J = 8.8Hz, 2.8Hz), 6.97-6.92 (3H, m), 5.39 (1H, d, J = 11.1Hz), 5.33 (1H, d, J = 11.1Hz), 4.51-4 .45 (1H, m), 4.12-4.05 (1H, m), 3.65-3.55 ( 1H, m), 3.44-3.38 (2H, m), 3.30-3.20 (1H, m ), 3.09-3.01 (1H, m), 0.88-0.77 (2H, m), -0 .08 (9H, s).

[0317] Step 2: 1,1-Diphenyl-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]methanymine 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman under a nitrogen atmosphere To a solution of -3-yl]-4-phenylimidazole-1-yl]methoxy]ethyl-trimethyl-silane (444 mg, 0.83 mmol), benzophenone imine (210 μL, 1.25 mmol), and Cs2CO3 (677.1 mg, 2.08 mmol) in dried 1,4-dioxane (4 mL), (+ / -)-BINAP (103.5 mg, 0.17 mmol) and tris(dibenzylideneacetone)dipalladium (0) (76.1 mg, 0.08 mmol) were added, and the mixture was heated at 110 °C for 18 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtered solid was washed with SiO2. The solvent was removed under vacuum, and the residue was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-100% to obtain 1,1-diphenyl-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]methanymine (564.3 mg, 0.83 mmol, 100% yield) as an orange solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 2.12 min, m / z 679.5 [M+H] + .

[0318] Step 3: Acetate; 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine 1,1-diphenyl-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]methanymine (564.3 mg, 0.83 mmol) was added to a solution of MeOH (8.3 mL) with NaOH (204.6 mg, 2.49 mmol) and hydroxylamine hydrochloride (127.1 mg, 1.83 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-10% as the eluent to obtain acetic acid;4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (366.4 mg, 0.64 mmol, yield 77%) as an orange solid. UPLC-MS (ES+, low acidity): 1.70 min, m / z 515.4 [ M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 7.79-7.72 (4H, m), 7.38-7.32 (2H, m), 7.22-7.17 (1H, m), 7.00-6.97 (1H, m), 6.92-6.89 (2H, m), 6.13 (1H, dd, J = 5.9Hz, 2.3Hz), 5.96 (2 H, br s), 5.82 (1H, d, J = 2.3Hz), 5.48 (1H, d, J = 11.1Hz), 5.42 (1H, d, J = 11.1Hz), 4.49-4.43 (1H, m), 4.07-4.00 (1H, m), 3.60-3.48 (3H, m), 3.35-3.28 (1H, m, (partially below water peak)), 3.07-2.99 (1H, m), 1.91 (3H, s, AcOH), 0.94 -0.83 (2H, m), -0.02 (9H, s).

[0319] Step 4 2,2-difluoro-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide Under a nitrogen atmosphere, 2,2-difluorocyclopropanecarboxylic acid (63.7 mg, 0.52 mmol) was added to a solution of anhydrous THF (0.7 mL) at 0°C to DMF (2 μL, 0.0300 mmol) and oxalyl chloride (44.6 μL, 0.53 mmol), and the reaction mixture was stirred at 0°C for 30 minutes. Next, the mixture was added to a solution of acetate; 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (60 mg, 0.10 mmol) in anhydrous pyridine (0.70 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with RINKAN (30 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was removed by vacuum. Gradient 0-10 The residue was purified by column chromatography using 0% siRNA / petroleum ether as the eluent to obtain 2,2-difluoro-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide (47.3 mg, 0.076 mmol, yield 73%) as a glassy solid. UPLC-MS (ES+, low acidity): 2.06 min, m / z 619.5 [M+H] + . 1 1H NMR (400MHz, DMSO) -d6) δ / ppm: 11.03 (1H, s), 8.20 (1H, d, J = 5.7Hz), 7.77 (1H, s), 7.76-7.72 (2H, m), 7.6 2 (1H, br s), 7.37-7.32 (2H, m), 7.22-7.16 (1H, m), 7.05 (1H, d, J = 2.6Hz), 6.96 (1H, dd, J = 8.8Hz, 2.6Hz), 6.92 (1H, d, J = 8.8Hz), 6.67 (1H, ddd, J = 5.7Hz, 4.1Hz, 2.3Hz), 5. 48 (1H, d, J = 11.1Hz), 5.42 (1H, d, J = 11.1 Hz), 5.50-5.44 (1H, m), 4.05 (1H, td, J = 10 .7Hz, 1.7Hz), 3.60-3.54 (3H, m), 3.32-3.25 (1H, m), 3.07-2.90 (2H, m), 2.04-1.93 (2H, m), 0.93-0.85 (2H, m), -0.03 (9H, s).

[0320] Step 5: 2,2-difluoro-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide 2,2-difluoro-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide (47.3 mg, 0.08 mmol) was added to a solution of DCM (1 mL) with trifluoroacetic acid (0.5 mL, 6.53 mmol), and the mixture was stirred at room temperature for 72 hours. The solvent was removed by vacuum, and the residue was loaded onto an SCX-2 column, which was then flushed with MeOH (10 mL) and then with NH3 in MeOH (10 mL) to elute the product. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-6% as the eluent to obtain 2,2-difluoro-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]cyclopropanecarboxamide (28.8 mg, 0.059 mmol, yield 77%) as a white solid. UPLC-MS (ES+, final purity): 2.94 min, m / z 489.3 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.32 (0.2H, br s), 12.10 (0.8H, br s), 11 .03 (1H, s), 8.19 (1H, d, J = 5.7Hz), 7.79-7 .56 (3.78H, m), 7.44-7.12 (3.22, m), 7.06-7.03 (1H, m), 6.94 (1H, dd, J = 8.8Hz, 2.8Hz) , 6.90 (1H, d, J = 8.8Hz), 6.67 (1H, ddd, J = 5.7Hz, 2.3Hz, 0.7Hz), 4.55-4.49 (1H, m), 4.17-4.09 (1H, m), 3.45-3.36 (1H, m), 3.29-3.19 (1H, m), 3.18-3.07 (1H, m), 3.01-2.90 (1 H, m), 2.05-1.91 (2H, m).

[0321] In step 4, the compounds listed in the table below were prepared using the appropriate acid in a similar manner. [Table 23-1] [Table 23-2]

[0322] Example 34. Synthesis of N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]acetamide (compound 156) [ka] Step 1: N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]acetamide Acetic acid; a solution of 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (69.5 mg, 0.12 mmol) in pyridine (0.6 mL) was gradually added to a solution of anhydrous acetic acid (23 μL, 0.24 mmol) in THF (0.6 mL), and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with Depositphotos (30 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using siRNA / petroleum ether as the eluent with a gradient of 0-100%, yielding N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]acetamide (47.5 mg, 0.085 mmol, yield 71%) as a white solid. UPLC-MS (ES+, low acidity): 1.90 min, m / z 557.5 [M+H] + . 1 1H NMR (400MHz, DM) SO-d6) δ / ppm: 10.50 (1H, s), 8.15 (1H, d, J = 5.7Hz), 7.77 (1H, s), 7.76-7.72 (2H, m), 7.66 (1H, d, J = 2.1Hz), 7.38-7.32 (2H, m), 7 .22-7.17 (1H, m), 7.02 (1H, d, J = 2.4Hz), 6 .97-6.90 (2H, m), 6.60 (1H, dd, J = 5.7Hz, 2 .4Hz), 5.49 (1H, d, J = 11.1Hz), 5.42 (1H, d , J = 11.1Hz), 4.50-4.43 (1H, m), 4.09-4.01 (1H, m), 3.61-3.50 (3H, m), 3.31-3.25 (1H, m), 3.07-2.98 (1H, m), 2.05 (3H, s), 0.93-0 0.86 (2H, m), -0.02 (9H, s).

[0323] Step 2: N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]acetamide To a solution of N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]acetamide (39.4 mg, 0.07 mmol) in DCM (1 mL), TFA (0.5 mL, 6.53 mmol) was added, and the mixture was stirred at room temperature for 22 hours. The solvent was removed under reduced pressure, and the residue was loaded onto an SCX-2 column. The product was eluted by flushing first with MeOH (10 mL) and then with NH3 in MeOH (10 mL). The solvent was removed under vacuum, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-8% as the eluent to obtain N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]acetamide (20.2 mg, 0.047 mmol, yield 70%) as a white solid. UPLC-MS (ES+, final purity): 2.45 min, m / z 427.2 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ / ppm: 12.32 (0.2, br s), 12.10 (0.8H, br s), 10.50 (1H, s), 8.15 (1H, d, J = 5.7Hz), 7.78-7.73 (1.6H, m), 7.68-7.57 (2.2H, m), 7.43-7.37 (0.4H, m), 7.36-7.29 (1.6H, m), 7.29-7.20 (0.4H, m), 7.18-7.13 (0.8H, m), 7.05-7.01 (1H, m), 6.93 (1H, dd, J = 8.8Hz, 2.7Hz), 6.89 (1H, d, J = 8.8Hz), 6.60 (1H, dd, J = 5. 7Hz, 2.4Hz), 4.55-4.49 (1H, m), 4.16-4.08 (1H, m), 3.45-3.35 (1H, m), 3.29-3.19 (1H, m ), 3.16-3.07 (1H, m), 2.05 (3H, s).

[0324] Example 35. Synthesis of N-cyclopropyl-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine-2-carboxamide (compound 158) [ka] Step 1: 4-Chloro-N-cyclopropyl-pyridine-2-carboxamide To a suspension of 4-chloro-2-pyridinecarboxylic acid (500 mg, 3.17 mmol) and cyclopropylamine (242 μL, 3.49 mmol) in THF (32 mL), T3P (2.8 mL, 4.7 mmol) and DIPEA (1.1 mL, 6.32 mmol) were added, and the mixture was heated at 65°C for 2.5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in RINKAN (100 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (25 mL), water (2 × 25 mL), and brine (25 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain 4-chloro-N-cyclopropyl-pyridine-2-carboxamide (499.8 mg, 2.54 mmol, yield 80%) as an off-white solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.35 min, m / z 197.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ / ppm: 8.82 (1H, d, J = 4.4Hz), 8.59 (1H, dd, J = 5.3, 0.6Hz), 8.01 (1H, dd, J = 2.2Hz, 0.6Hz), 7.75 (1H, dd, J = 5.3Hz, 2.2Hz), 2.95-2.87 (1H, m), 0.72-0.65 (4H, m).

[0325] Step 2: 6-[[2-(cyclopropylcarbamoyl)-4-pyridyl]oxy]chroman-3-carboxylic acid To a solution of 4-chloro-N-cyclopropylpyridine-2-carboxamide (200 mg, 1.02 mmol) in DMF (10 mL) under a nitrogen atmosphere, Cs2CO3 (994.3 mg, 3.05 mmol) and 6-hydroxychroman-3-carboxylic acid (197.8 mg, 1.02 mmol) were added, and the mixture was heated overnight at 100°C. Additional 6-hydroxychroman-3-carboxylic acid (49.4 mg, 0.25 mmol) and Cs2CO3 (165.7 mg, 0.51 mmol) were added, and the mixture was heated at 100°C for 72 hours. After cooling to room temperature, the mixture was poured into cold water, and the aqueous solution was acidified to pH 2 with 1N aqueous HCl solution, followed by siRNA (4 × 50 mL). The combined organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-10% as the eluent, and 6-[[2-(cyclopropyl Carbamoyl)-4-pyridyl]oxy]chroman-3-carboxylic acid (192.9 mg, 0.54 mmol, 54% yield) was obtained as a light brown solid. UPLC-MS (ES+, low acidity): 1.47 min, m / z 355.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ / ppm: 12.69 (1H, s), 8.71 (1 H, d, J = 5.0Hz), 8.47 (1H, dd, J = 5.6Hz, 0. 4Hz), 7.34 (1H, dd, J = 2.7Hz, 0.4Hz), 7.12 (1H, dd, J = 5.6Hz, 2.7Hz), 7.04 (1H, d, J = 2.8Hz), 6.94 (1H, dd, J = 8.8Hz, 2.8Hz), 6.88 (1H, d, J = 8.8Hz), 4.36 (1H, dd, J = 10.8H z, 3.1Hz), 4.17 (1H, dd, J = 10.8Hz, 7.7Hz), 3.06-2.95 (3H, m), 2.89-2.82 (1H, m), 0.69 -0.63 (4H, m).

[0326] Step 3: N-cyclopropyl-4-[3-(phenacylcarbamoyl)croman-6-yl]oxypyridine-2-carboxamide To a solution of 6-[[2-(cyclopropylcarbamoyl)-4-pyridyl]oxy]chroman-3-carboxylic acid (190.6 mg, 0.54 mmol) and 2-aminoacetophenone hydrochloride (101.6 mg, 0.59 mmol) in THF (5.3 mL), T3P (480 μL, 0.81 mmol) and DIPEA (290 μL, 1.66 mmol) were added, and the mixture was heated at 65 °C for 2 hours. After cooling to room temperature, the solvent was removed by vacuum, and the residue was dissolved in SiO (50 mL). The organic layer was washed with water (2 × 15 mL) and brine (15 mL), dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was suspended in petroleum ether, filtered, and dried to obtain N-cyclopropyl-4-[3-(phenacylcarbamoyl)croman-6-yl]oxypyridine-2-carboxamide (228 mg, 0.48 mmol, 90% yield) as a cream-colored solid. UPLC-MS (ES+, low acidity): 1.64 min, m / z 472.5 [M+H] + . 1 HN MR (400MHz, DMSO-d6) δ / ppm: 8.72 (1H, d, J = 5.0Hz), 8.58-8.53 (1H, m), 8.47 (1H, dd, J = 5.6Hz, 0.3Hz), 8.02-7.97 (2H, m), 7.70-7.65 (1H, m), 7.58-7.52 (2H, m), 7.35 (1H, dd, J = 2.6Hz, 0.3Hz), 7.13 (1H, dd, J = 5.6Hz, 2.6Hz), 7.06 (1H, d, J = 2.8Hz), 6.96 (1H, d d, J = 8.8Hz, 2.8Hz), 6.90 (1H, d, J = 8.8Hz), 4.67 (2H, d, J = 5.6Hz), 4.43-4.37 (1H, m) , 4.03-3.95 (1H, m), 3.07-2.82 (4H, m), 0.6 9-0.62 (4H, m).

[0327] Step 4 N-Cyclopropyl-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine-2-carboxamide A suspension of N-cyclopropyl-4-[3-(phenacylcarbamoyl)chroman-6-yl]oxypyridine-2-carboxamide (227.6 mg, 0.48 mmol) in 1-butanol (4.8 mL) was mixed with ammonium acetate (372.1 mg, 4.82 mmol) and triethylamine (67 μL, 0.48 mmol), and the mixture was irradiated at 150°C for 45 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-4% as the eluent. Subsequently, the residue was purified by reverse-phase column chromatography using (MeCN + 0.1% formic acid) with a gradient of 0-50% as the eluent in (water + 0.1% formic acid). The fractions containing the product were combined, the solvent was removed under vacuum, and the residue was loaded into an SCX-2. The product was eluted by flushing it first with MeOH, and then with MeOH + NH3. Remove the solvent under vacuum and then N-cyclopropyl-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyryl Zin-2-carboxamide (75.7 mg, 0.17 mmol, 67% yield) was obtained as a white solid. UPLC-MS (ES+, final purity): 3.12 min, m / z 453.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.24 (1H, br s), 8.72 (1H, d, J = 5.0Hz), 8.47 (1H, dd, J = 5.6Hz, 0.3Hz), 7.76-7.70 (2H, m), 7.55 (1H, br s), 7.39-7.32 (3H, m), 7.22-7.16 (1H, m), 7.15 (1H, dd, J = 5.6Hz, 2.6Hz ), 7.09 (1H, d, J = 2.8Hz), 6.99 (1H, dd, J = 8.8Hz, 2.8Hz), 6.94 (1H, d, J = 8.8Hz), 4.57-4.51 (1H, m), 4.20-4.13 (1H, m), 3.49-3.39 (1H, m), 3.30-3.22 (1H, m), 3.19-3.10 (1H, m), 2.91-2.82 (1H, m), 0.71-0.62 (4H, m).

[0328] Example 36. Synthesis of N-cyclobutyl-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine-2-amine (Compound 142) [ka] Step 1: N-Cyclobutyl-4-[3-[5-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine A solution of 2-[[2-[6-[(2-chloro-4-pyridyl)oxy]chroman-3-yl]-5-phenylimidazole-1-yl]methoxy]ethyl-trimethyl-silane (125 mg, 0.23 mmol; Example 33, Step 1), tris(dibenzylideneacetone)dipalladium(0) (21.5 mg, 0.02 mmol), (+ / -)-BINAP (29.2 mg, 0.05 mmol), and Cs2CO3 (152.5 mg, 0.47 mmol) in 1,4-dioxane (2.2 mL) was degassed under a nitrogen atmosphere for 10 minutes, and then cyclobutanamine (40 μL, 0.47 mmol) was added. The vial was sealed and the mixture was heated at 100 °C for 20 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtered solids were washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography using 0-10% MeOH / DCM as the eluent to obtain N-cyclobutyl-4-[3-[5-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (133.1 mg, 0.23 mmol, 100% yield) as an orange foam. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.83 min, m / z 569.3 [M+H] + .

[0329] Step 2: N-Cyclobutyl-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine-2-amine To a solution of N-cyclobutyl-4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (133.1 mg, 0.23 mmol) in DCM (3.6 mL), TFA (1.8 mL, 23.51 mmol) was added, and the mixture was stirred at 25°C for 18 hours. The solvent was removed under reduced pressure, and the residue was loaded onto an SCX-2 column, first with MeOH (10 mL), then with MeOH. The product was eluted by flushing with NH3 in OH (10 mL). The residue was purified by column chromatography using a 0-6% MeOH / DCM gradient as the eluent, followed by reverse-phase column chromatography using a 0-50% (MeCN + 0.1% formic acid) gradient in (water + 0.1% formic acid) as the eluent. The fraction containing the product was loaded onto an SCX-2 column and flushed first with MeOH (10 mL), then with NH3 in MeOH (10 mL) to obtain N-cyclobutyl-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine-2-amine (30 mg, 0.068 mmol, yield 29%) as a white solid. ULC-MS (ES+, final Purity): 2.45 min, m / z 439.2 [M+H] + . 1 1H NMR (400MH) z, DMSO-d6) δ / ppm: 12.12 (1H, br s), 7.82 (1H, d, J = 5.8Hz), 7.73 (2H, m), 7.55 (1H, br s), 7.38-7.30 (2H, m), 7.21-7.14 (1H, m), 6 .99-6.96 (1H, m), 6.91-6.85 (2H, m), 6.77 ( 1H, d, J = 6.6Hz, broad), 6.10 (1H, dd, J = 5 .8, 2.2Hz), 5.76 (1H, d, J = 2.2Hz), 4.54-4.48 (1H, m), 4.27-4.15 (1H, m), 4.15-4.06 (1 H, m), 3.43-3.34 (1H, m), 3.28-3.19 (1H, m) , 3.15-3.07 (1H, m), 2.25-2.16 (2H, m), 1.8 5-1.73 (2H, m), 1.69-1.53 ​​(2H, m).

[0330] Example 37. Synthesis of 1-methyl-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]piperidine-4-carboxamide (compound 147) [ka] Step 1 1-Methyl-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]piperidine-4-carboxamide A solution of 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (60 mg, 0.12 mmol), 1-methylpiperidine-4-carboxylic acid (18.4 mg, 0.13 mmol), propylphosphonic anhydride (104 μL, 0.17 mmol), and N,N-diisopropylethylamine (41 μL, 0.23 mmol) in THF (1.2 mL) was heated overnight at 65°C in a sealed tube. Additional 1-methylpiperidine-4-carboxylic acid (18.4 mg, 0.13 mmol), propylphosphonic anhydride (104 μL, 0.17 mmol), and N,N-diisopropylethylamine (41 μL, 0.23 mmol) were added to a sealable vial. The vial was sealed and the mixture was heated at 65°C for 2 hours. After cooling to room temperature, the mixture was concentrated and the residue was purified by column chromatography using 0-20% MeOH / DCM followed by NH3(2N) / MeOH with a 20% gradient as the eluent to obtain 1-methyl-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]piperidine-4-carboxamide (38.4 mg, 0.060 mmol, A yield of 51% was obtained as an off-white solid. UPLC-MS (ES+, low acidity) : 1.71 min, m / z 640.3 [M+H] + .

[0331] Step 2: 1-Methyl-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]piperidine-4-carboxamide 1-methyl-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]piperidine-4-carboxamide (38.4 mg, 0.060 mmol) was added to a solution of DCM (1 mL) to trifluoroacetic acid (0.5 mL, 6.53 mmol) in a sealable vial. The vial was sealed and the mixture was stirred at 25°C for 18 hours. The mixture was concentrated and the residue was purified by reverse-phase column chromatography using acetonitrile + 0.1% formic acid / water + 0.1% formic acid as the eluent with a gradient of 0-50%. The fractions containing the product were combined, the solvent was removed by vacuum, and the mixture was loaded onto an SCX-2 column. The column was washed first with MeOH, then with MeOH+NH3 to obtain 1-methyl-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]piperidine-4-carboxamide (16 mg, 0.031 mmol, 52% yield) as a white solid. UPLC-MS (ES+, final purity): 2.26 min, m / z 510.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.31 (0.2H, br s), 12.09 (0.8H, br s), 10.45 (1H, s), 8.15 (1H, d, J = 5.7Hz), 7.77-7.73 (1.6H, m), 7.67 (1H, d, J = 2.4Hz), 7.66-7.61 (0.4H, m ), 7.61-7.57 (0.8H, m), 7.43-7.37 (0.4H, m), 7.36-7.29 (1.6H, m), 7.29-7.20 (0.4H, m), 7.19-7.13 (0.8H, m), 7.04-7.01 (1H, m), 6. 93 (1H, dd, J = 8.8, 2.6Hz), 6.90 (1H, d, J = 8.8Hz), 6.62 (1H, dd, J = 5.7, 2.4Hz), 4.56-4.49 (1H, m), 4.17-4.09 (1H, m), 3.46-3.36 (1H, m), 3.29-3.20 (1H, m), 3.17-3.07 (1H, m), 2.85-2.75 (2H, m), 2.43-2.36 (1H, m), 2 .16 (3H, s), 1.92-1.69 (2H, m), 1.74-1.65 ( 2H, m), 1.64-1.51 (2H, m).

[0332] The compounds shown in the table below were prepared in a similar manner using the appropriate acid in Step 1. [Table 24]

[0333] Example 38. 2-(4-methylpiperazine-1-yl)-N-[4-[3 Synthesis of Nyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]acetamide (compound 146) [ka] Step 1: 2-(4-methylpiperazine-1-yl)-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]acetamide Under a nitrogen atmosphere at 0°C, a solution of 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (100 mg, 0.19 mmol) and Et3N (68 μL, 0.49 mmol) in anhydrous THF (2 mL) was gradually added to a solution of chloroacetyl chloride (16 μL, 0.20 mmol) in THF (0.5 mL), and the mixture was stirred at 25°C for 1 hour. Next, a solution of 1-methylpiperazine (26 μL, 0.23 mmol) in anhydrous THF (0.5 mL) was added dropwise, and the mixture was stirred at 25°C for 18 hours. An additional 1-methylpiperazine (26 μL, 0.23 mmol) was added, and the mixture was heated at 65°C for 4 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-20% as the eluent to obtain 2-(4-methylpiperazin-1-yl)-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]acetamide (50.5 mg, 0.077 mmol, yield 40%) as a yellow solid. UPLC-MS (ES+, low acidity): 1.68 min, m / z 655.4 [M+H] + .

[0334] Step 2: 2-(4-methylpiperazine-1-yl)-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]acetamide To a solution of 2-(4-methylpiperazin-1-yl)-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]acetamide (49.3 mg, 0.0800 mmol) in DCM (1.2 mL), trifluoroacetic acid (0.6 mL, 7.84 mmol) was added, and the mixture was stirred in a sealed tube at 25°C for 22 hours. The mixture was concentrated, and the residue was purified by flash chromatography (C18, 12 g column, gradient 0-50% MeCN / H2O + 0.1% HCO2H). The pure fraction was loaded onto a pre-equilibrated SCX-2 column using methanol. The column was washed with methanol, and the filtrate was discarded. Next, the product was eluted with NH3(2N) / methanol, and the filtrate was concentrated to obtain 2-(4-methylpiperazin-1-yl)-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)]chroman-6-yl]oxy-2-pyridyl]acetamide (26 mg, 0.050 mmol, yield 66%) as a white solid. UPLC-MS (ES+, final) Purity): 2.29 min, m / z 525.3 [M+H] + . 1 1H NMR (400MH) z, DMSO-d6) δ / ppm: 12.31 (0.2H, br s), 12.0 9 (0.8H, br s), 9.89 (1H, s), 8.17 (1H, d, J = 5.8Hz), 7.77-7.73 (1.6H, m), 7.66 (1H, d, J = 2.4Hz), 7.65-7.61 (0.4H, m), 7.61-7.57 (0.8H, m), 7.43-7.37 (0.4H, m), 7.36-7.29 (1.6H, m), 7.29-7.20 (0.4H, m), 7.19-7.13 (0.8H, m), 7.06-7.02 (1H, m), 6.94 (1H, dd, J = 8.8, 2.7Hz), 6.90 (1H, d, J = 8.8Hz), 6.66 (1H, dd, J = 5.8, 2.4Hz), 4.55-4.49 (1H, m), 4.17-4.09 (1H, m), 3.45-3.35 (1H, m), 3.26 -3.19 (1H, m), 3.16-3.07 (3H, m), 2.37 (4H, m, seen as br s), 2.18 (3H, s). 4H disappears (below the DMSO / water peak).

[0335] Using the appropriate amine in Step 1, the compounds listed in the table below were prepared in a similar manner. [Table 25-1] [Table 25-2]

[0336] Example 39. Synthesis of 2-morpholino-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]propenamide (compound 150) [ka] Step 1: 2-Morpholino-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]propanamide Under a nitrogen atmosphere, a solution of 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyridine-2-amine (68 mg, 0.13 mmol) and triethylamine (55 μL, 0.40 mmol) in anhydrous THF (1.3 mL) was gradually added to a solution of chloropropionyl chloride (16 μL, 0.16 mmol) in anhydrous THF (0.5 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. Morpholine (23 μL, 0.26 mmol) and sodium iodide (40 mg, 0.26 mmol) were added to this mixture, and the reaction was heated at 60°C for 72 hours. After cooling to room temperature, the mixture was concentrated, and a MeOH / DCM gradient of 0-4% was used as the eluent. The residue was purified by column chromatography to obtain 2-morpholino-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]propanamide (43 mg, 0.065 mmol, yield 49%) as an off-white solid. UPLC-MS (ES+, low acidity): 1.82 min, m / z 656.5 [M+H] + .

[0337] Step 2: 2-Morpholino-N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxy-2-pyridyl]propenamide To a solution of 2-morpholino-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]propanamide (42 mg, 0.06 mmol) in DCM (1 mL), trifluoroacetic acid (490 μL, 6.4 mmol) was added, and the mixture was stirred in a sealed tube at 25°C for 22 hours. The mixture was concentrated, and the residue was purified by column chromatography using a gradient of 0-50% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid) as the eluent. The fraction containing the product was loaded onto an SCX-2 column and flushed with MeOH, then with MeOH+NH3 to obtain 2-morpholino-N-[4-[3-(4-phenyl-1H-imidazole-2-yl]chroman-6-yl]oxy-2-pyridyl]propanamide (23 mg, 0.043 mmol, yield 68%) as a white solid. UPLC-MS (ES+, final purity): 2.46 min, m / z 526.3 [M+H] + . 1 H NM R (400MHz, DMSO-d6) δ / ppm: 12.16 (1H, br s) , 10.13 (1H, s), 8.17 (1H, d, J = 5.7Hz), 7.76-7.70 (2H, m), 7.68 (1H, d, J = 2.3Hz), 7.5 4 (1H, br s), 7.38-7.31 (2H, m), 7.21-7.15 (1H, m), 7.04 (1H, d, J = 2.7Hz), 6.94 (1H, dd, J = 8.8Hz, 2.7Hz), 6.90 (1H, d, J = 8.8Hz), 6.66 (1H, dd, J = 5.7Hz, 2.3Hz), 4.56-4.50 (1H, m), 4.18-4.10 (1H, m), 3.65-3.56 (4H, m), 3.46-3.35 (2H, m), 3.30-3.08 (2H, m), 1 0.15 (3H, d, J = 6.7Hz). 4H disappears (below DMSO or water peak) .

[0338] Example 40. Synthesis of N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide (compound 148) [ka] Step 1: 4-Chloro-6-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-amine A mixture of 4,6-dichloropyrimidine-2-amine (51.2 mg, 0.31 mmol), 3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-ol (132 mg, 0.31 mmol), and Cs2CO3 (152.6 mg, 0.47 mmol) in DMF (1.5 mL) was heated overnight at 60°C. After cooling to room temperature, the mixture was poured into water (30 mL), and the aqueous solution was extracted with Depositphotos (5 × 20 mL), followed by Depositphotos:MeOH (10:1, 5 × 20 mL). The combined organic extract was dried over Na2SO4, filtered, and the solvent was removed by vacuum. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-4% as the eluent to obtain 4-chloro-6-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-amine (120 mg, 0.22 mmol, yield 70%) as a white foam. UPLC-MS (ES+, low acidity): 2.10 minutes, m / z 550.5 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ / ppm: 7.77 (1H, s), 7.7 6-7.72 (2H, m), 7.38-7.32 (2H, m), 7.22-7.17 (1H, m), 7.13 (2H, br s), 7.01 (1H, d, J = 2.8Hz), 6.95 (1H, dd, J = 8.8, 2.8Hz), 6.87 ( 1H, d, J = 8.8Hz), 6.13 (1H, s), 5.45 (2H, m), 4.49-4.42 (1H, m), 4.08-4.00 (1H, m), 3.6 3-3.46 (3H, m), 3.31-3.23 (1H, m), 3.07-2.97 (1H, m), 0.94-0.85 (2H, m), -0.02 (9H, s).

[0339] Step 2: 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-amine 4-chloro-6-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-amine (119 mg, 0.22 mmol) and triethylamine (33 μL) in THF (7 mL) Palladium (10 wt.% on carbon powder, wet (57.5 mg, 0.05 mmol)) was added to a mixture of 0.24 mmol. An H2 balloon was attached to the reaction, excess H2 was added, and three vacuum / H2 cycles were performed. The mixture was then stirred under an H2 atmosphere for 72 hours. The mixture was filtered through a diatomaceous earth plug, and the filtrate was washed with THF and MeOH. The filtrate was concentrated, and the residue was partitioned between HCl (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with HCl (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-amine (111.5 mg, 0.22 mmol, 100% yield) as a white foam. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.75 min, m / z 516.5 [M+H] + .

[0340] Step 3 N-(cyclopropanecarbonyl)-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide To a solution of 4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-amine (111.5 mg, 0.22 mmol) in pyridine (1.6 mL) and DCM (1.1 mL), cyclopropane carbonyl chloride (25 μL, 0.27 mmol) in DCM (0.1 mL) was added dropwise, and the mixture was stirred under a nitrogen atmosphere at 25°C for 18 hours. A solution of cyclopropane carbonyl chloride (98 μL, 1.08 mmol) in DCM (0.1 mL) was gradually added, and the mixture was stirred at 25°C for 5 hours. The crude product was diluted with DCM (30 mL), washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-40% as the eluent to obtain N-(cyclopropanecarbonyl)-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide (101 mg, 0.16 mmol, yield 72%) as a colorless oil, which solidified upon standing. UPLC-MS (ES+, low acidity): 2.14 min, m / z 652.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 8.76 (1H, d, J = 5.8Hz), 7.77 (1H, s), 7.77-7.72 (2H, m), 7.38-7.32 (2H, m), 7.23-7.16 (1H, m), 7.13 (1H, d, J = 5.8Hz), 7.07 (1H, d, J = 2.8Hz), 7.00 (1H, dd, J = 8.8, 2.8Hz) , 6.91 (1H, d, J = 8.8Hz), 5.47 (1H, d, J = 11.1Hz), 5.43 (1H, d, J = 11.1Hz), 4.50-4.44 (1H, m), 4.09-4.02 (1H, m), 3.61-3.51 (3H, m ), 3.31-3.25 (1H, m), 3.06-2.97 (1H, m), 1. 95-1.87 (2H, m), 0.97-0.88 (10H, m), -0.02 (9H, s).

[0341] Step 4 N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]croman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide N-(cyclopropanecarbonyl)-N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide (96 mg, 0.15 mmol) was dissolved in NH3 (7 M in MeOH - 3 mL, 21 mmol), and the mixture was stirred at 25°C for 1 hour. The solvent was removed under reduced pressure, and siRNA / petroleum ether with a gradient of 0-80% was added as the eluent. Using column chromatography as the method, the residue was purified to obtain N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide (70 mg, 0.12 mmol, yield 82%) as a white solid. UPLC-MS (ES+ , low acidity): 1.97 min, m / z 584.4 [M+H] + . 1 1H NMR (40 0MHz, DMSO-d6) δ / ppm: 10.62 (1H, s), 8.47 ( 1H, d, J = 5.7Hz), 7.77 (1H, s), 7.77-7.72 ( 2H, m), 7.38-7.32 (2H, m), 7.22-7.17 (1H, m ), 7.10 (1H, d, J = 2.8Hz), 7.02 (1H, dd, J = 8.8, 2.8Hz), 6.89 (1H, d, J = 8.8Hz), 6.63 ( 1H, d, J = 5.7Hz), 5.47 (1H, d, J = 11.1Hz), 5.42 (1H, d, J = 11.1Hz), 4.50-4.43 (1H, m), 4.09-4.02 (1H, m), 3.61-3.54 (2H, m), 3.54 -3.47 (1H, m), 3.31-3.24 (1H, m), 3.07-2.98 (1H, m), 2.24-2.16 (1H, m), 0.93-0.86 (2H, m), 0.80-0.68 (4H, m), -0.02 (9H, s).

[0342] Step 5 N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide To a solution of N-[4-[3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide (69 mg, 0.12 mmol) in DCM (1.8 mL), trifluoroacetic acid (0.9 mL, 11.75 mmol) was added, and the mixture was stirred at 25°C for 18 hours. The mixture was concentrated, and the residue was loaded onto an SCX-2 column. This column was washed first with MeOH, and then with NH3 in MeOH, to elute the product. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0-8% as the eluent. The same fractions were pooled and concentrated to obtain N-[4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyrimidine-2-yl]cyclopropanecarboxamide (44 mg, 0.096 mmol, yield 82%) as a white solid. UPLC-MS (ES+, final purity): 2.65 min, m / z 454.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.32 (0.2H, br s), 12.10 (0.8H, br s), 10.62 (1H, s), 8. 46 (1H, d, J = 5.7Hz), 7.79-7.72 (1.6H, m), 7.67-7.56 (1.2H, m), 7.45-7.36 (0.4H, m), 7.36-7.29 (1.6H, m), 7.29-7.20 (0.4H, m), 7.20-7.12 (0.8H, m), 7.10 (1H, d, J = 2.8Hz), 7.00 (1H, dd, J = 8.8, 2.8Hz), 6.86 (1H, d, J = 8.8Hz), 6.63 (1H, d, J = 5.7Hz), 4.54-4.4 8 (1H, m), 4.15-4.06 (1H, m), 3.43-3.33 (1H , m), 3.29-3.18 (1H, m), 3.16-3.06 (1H, m), 2.23-2.15 (1H, m), 0.80-0.66 (4H, m).

[0343] Example 41. Synthesis of 2-(4-methyl-1H-imidazole-2-yl)-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine (compound 143) [ka] Step 1 tert-butyl6-[[2-[4-methyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]-4-pyridyl]oxy]chroman-3-carboxylate A mixture of 2-[[2-(4-bromo-2-pyridyl)-4-methyl-imidazole-1-yl]methoxy]ethyl-trimethyl-silane (285 mg, 0.77 mmol), tert-butyl 6-hydroxychroman-3-carboxylic acid (213 mg, 0.85 mmol), and tripotassium tribasic phosphate (328.5 mg, 1.55 mmol) in anhydrous toluene (3.8 mL) was degassed under a nitrogen atmosphere for 10 minutes; then, palladium(II) acetate (10.4 mg, 0.05 mmol) and 2-(di-tert-butylphosphino)biphenyl (27.7 mg, 0.09 mmol) were added. The vial was sealed and the mixture was heated at 100°C for 4 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth plug, and the filtered solid was washed with DCM. The filtrate was concentrated, and the residue was purified by column chromatography using siRNA / petroleum ether with a gradient of 0-100% as the eluent to obtain tert-butyl 6-[[2-[4-methyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]-4-pyridyl]oxy]chroman-3-carboxylate (330 mg, 0.61 mmol, yield 79%) as a dark orange oil. UPLC-MS (E S+, low acidity): 1.92 and 1.98 mins, m / z 538.8 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) (matches a positional isomer ratio of approximately 2.5 / 1) .

[0344] Step 2 Formic acid; 6-[[2-(4-methyl-1H-imidazole-2-yl)-4-pyridyl]oxy]chroman-3-carboxylic acid (0.4;1) 328 mg, 0.61 mmol of tert-butyl 6-[[2-[4-methyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-yl]-4-pyridyl]oxy]chroman-3-carboxylate (328 mg, 0.61 mmol) was added to a solution of DCM (4.6 mL) with trifluoroacetic acid (2.3 mL, 30.04 mmol), and the mixture was stirred overnight at room temperature in a sealed vial. The mixture was concentrated, and the residue was azeotropically removed with toluene. The residue was purified by reverse-phase column chromatography using acetonitrile + 0.1% formic acid / water + 0.1% formic acid as the eluent with a gradient of 0-50%, to obtain 6-[[2-(4-methyl-1H-imidazole-2-yl)-4-pyridyl]oxy]chroman-3-carboxylic acid (0.4;1) (148 mg, 0.40 mmol, yield 66%) as a white solid. UPLC-MS (ES + , low acidity): 1.14 min, m / z 352.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ / ppm: 13.26 (1H, br s), 12.7 2 (1H, br s), 8.47 (1H, d, J = 5.7Hz), 8.13 ( 0.4H, s, formate), 7.37 (1H, d, J = 2.3Hz), 7.05 (1H, d, J = 2.8Hz), 6.98-6.93 (3H, m), 6.88 (1H, d, J = 8.8Hz), 4.36 (1H, dd, J = 10 .8Hz, 3.1Hz), 4.17 (1H, dd, J = 10.8Hz, 7.7Hz), 3.07-2.95 (3H, m), 2.19 (3H, s).

[0345] Step 3 6-[[2-(4-methyl-1H-imidazole-2-yl)-4-pyridyl]oxy]-N-phenacyl-chroman-3-carboxamide A mixture of formic acid; 6-[[2-(4-methyl-1H-imidazole-2-yl)-4-pyridyl]oxy]chroman-3-carboxylic acid (0.4;1) (148 mg, 0.40 mmol), 2-aminoacetophenone hydrochloride (75.7 mg, 0.44 mmol), propylphosphonic anhydride (358 μL, 0.60 mmol), and N,N-diisopropylethylamine (245 μL, 1.41 mmol) in THF (4 mL) was heated at 65 °C for 2 hours. After cooling to room temperature, the mixture was concentrated, and the residue was dissolved in ELISA (30 mL). The organic layer was washed with water (2 × 10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and the solvent was removed under vacuum to obtain 6-[[2-(4-methyl-1H-imidazole-2-yl)-4-pyridyl]oxy]-N-phenacyl-chroman-3-carboxamide (188 mg, 0.40 mmol, 100% yield) as an orange solid. The compound was used in the next step without further purification. UPLC-MS (ES+ , low acidity): 1.33 min, m / z 469.5 [M+H] + .

[0346] Step 4: 2-(4-methyl-1H-imidazole-2-yl)-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine A suspension of 6-[[2-(4-methyl-1H-imidazole-2-yl)-4-pyridyl]oxy]-N-phenacyl-chroman-3-carboxamide (188 mg, 0.40 mmol) in 1-butanol (4 mL) was mixed with ammonium acetate (309 mg, 4.01 mmol) and Et3N (56 μL, 0.40 mmol). The vial was sealed and the mixture was irradiated at 150 °C for 45 minutes. After cooling to room temperature, the mixture was concentrated and the residue was purified by column chromatography using MeOH with a gradient of 0-20% as the eluent. The fractions containing the product were combined and re-purified by reverse-phase column chromatography using acetonitrile + 0.1% formic acid with a gradient as the eluent. The fraction containing the product was loaded onto an SCX-2 column and flushed with MeOH, followed by MeOH+NH3 to obtain 2-(4-methyl-1H-imidazole-2-yl)-4-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyridine (42 mg, 0.093 mmol, 23% yield) as a white solid. UPLC-MS (ES+, final purity): 2.35 min, m / z 450.2 [M+H] + . 1 1H NMR (400MHz, DM) SO-d6+ (few μL of CF3CO2D) δ / ppm: 8.65 (1H, d, J = 5.7Hz), 8.14 (1H, s), 7.84-7.80 (2H, m), 7.78 (1H, d, J = 2.3Hz), 7.58-7.51 (3H, m), 7. 49-7.43 (1H, m), 7.15-7.10 (2H, m), 7.07 (1 H, dd, J = 8.8Hz, 2.8Hz), 7.01 (1H, d, J = 8. 8Hz), 4.65-4.58 (1H, m), 4.40 (1H, dd, J = 1 0.7Hz, 9.0Hz), 3.91-3.82 (1H, m), 3.44-3.2 7 (2H, m), 2.33 (3H, d, J = 0.9Hz).

[0347] Example 42. Synthesis of 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxy-N-phenacyl-chroman-3-carboxamide (compound 151) [ka] Step 1: N-(6-chloropyrimidine-4-yl)cyclopropanecarboxamide Under a nitrogen atmosphere, cyclopropane carbonyl chloride (0.7 mL, 7.71 mmol) was gradually added to a THF (25 mL) solution of 6-chloropyrimidine-4-ylamine (800 mg, 6.18 mmol) and pyridine (1.25 mL, 15.46 mmol) at 0°C, and the mixture was heated at 60°C for 17 hours. After cooling to room temperature, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography using MeOH / DCM with a gradient of 0–4% as the eluent to obtain N-(6-chloropyrimidine-4-yl)cyclopropanecarboxamide (917 mg, 4.64 mmol, yield 75%) as a white solid. UPLC-MS (ES+, low acidity): 1.35 min, m / z 197.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ / ppm: 11.54 (1H, s), 8.75 (1H, d, J = 1.0Hz), 8.10 (1H, d, J = 1.0Hz), 2.08-2.00 (1H, m), 0. 93-0.86 (4H, m).

[0348] Step 2: 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxychroman-3-carboxylic acid A solution of 6-hydroxychroman-3-carboxylic acid (198 mg, 1.02 mmol), N-(6-chloropyrimidine-4-yl)cyclopropanecarboxamide (200 mg, 1.01 mmol), and potassium carbonate (560 mg, 4.05 mmol) in DMSO (1.25 mL) was heated overnight at 110 °C. The reaction mixture was cooled to room temperature and poured into a solution of citric acid (777.8 mg, 4.05 mmol) in water (15 mL). The resulting precipitate was filtered, washed with water, and dried to obtain 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxychroman-3-carboxylic acid (316 mg, 0.89 mmol, yield 88%) as a light brown solid. The compound was used directly in the next step without further purification. UPLC-MS (ES+, low acidity): 1.44 min, m / z 356.2 [M+H] + (94%) 1 1H NMR (400MHz, DMSO-d6) δ / p pm: 12.67 (1H, br s), 11.22 (1H, s), 8.48 (1 H, d, J = 0.9Hz), 7.50 (1H, d, J = 0.9Hz), 6. 98 (1H, d, J = 2.8Hz), 6.89 (1H, dd, J = 8.8, 2.8Hz), 6.80 (1H, d, J = 8.8Hz), 4.32 (1H, d d, J = 10.8, 3.1Hz), 4.15 (1H, dd, J = 10.8, 7.5Hz), 3.04-2.92 (3H, m), 2.06-1.98 (1H, m), 0.89-0.80 (4H, m).

[0349] Step 3: 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxy-N-phenacyl-chroman-3-carboxamide A mixture of 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxychroman-3-carboxylic acid (100 mg, 0.28 mmol), 2-aminoacetophenone hydrochloride (53 mg, 0.31 mmol), propylphosphonic anhydride (250 μL, 0.42 mmol), and N,N-diisopropylethylamine (152 μL, 0.87 mmol) in THF (2.8 mL) was heated at 65 °C for 1 hour. After cooling to room temperature, the mixture was concentrated, and the residue was dissolved in ELISA (30 mL). The organic layer was washed with water (2 × 10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxy-N-phenacyl-chroman-3-carboxamide (131 mg, 0.28 mmol, 98% yield) as a light brown solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 1.61 min, m / z 473.2 [ M+H] + .

[0350] Step 4 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxy-N-phenacyl-chroman-3-carboxamide Ammonium acetate (213 mg, 2.77 mmol) and triethylamine (39 μL, 0.28 mmol) were added to a suspension of 6-[6-(cyclopropanecarbonylamino)pyrimidine-4-yl]oxy-N-phenacyl-chroman-3-carboxamide (131 mg, 0.28 mmol) in 1-butanol (2.7 mL). The vial was sealed and the mixture was irradiated at 150 °C for 45 minutes. The mixture was concentrated, and the residue was purified by column chromatography using MeOH / DCM as the eluent with a gradient of 0-20%. The fraction containing the product was re-purified by reverse-phase column chromatography using acetonitrile + 0.1% formic acid / water + 0.1% formic acid as the eluent with a gradient of 0-40%. The fraction containing the product was loaded onto an SCX-2 column and flushed first with MeOH and MeOH / NH3 to obtain N-[6-[3-(4-phenyl-1H-imidazole-2-yl)chroman-6-yl]oxypyrimidine-4-yl]cyclopropanecarboxamide (28 mg, 0.062 mmol, yield 22%) as a white solid. UPLC-MS (ES+ , final purity): 2.94 min, m / z 454.3 [M+H] + . 1 1H NMR (40 0MHz, DMSO-d6) δ / ppm: 12.30 (1H, br s), 11. 23 (1H, s), 8.50 (1H, d, J = 1.0Hz), 7.76-7. 70 (2H, m), 7.56 (1H, br s), 7.52 (1H, d, J = 1.0Hz), 7.38-7.32 (2H, m), 7.22-7.16 (1H, m), 7.03 (1H, d, J = 2.8Hz), 6.94 (1H, dd, J = 8.8Hz, 2.8Hz), 6.86 (1H, d, J = 8.8Hz), 4.55-4.49 (1H, m), 4.18-4.10 (1H, m), 3.47-3.38 (1H, m), 3.29-3.19 (1H, m), 3.16-3.08 (1H, m), 2.07-1.99 (1H, m), 0.89-0.82 (4H, m).

[0351] Example 43. Synthesis of 5-[3-(5-isopropyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 133) [ka] Step 1: tert-butyl 4-hydroxyiminopiperidine-1-carboxylate A mixture of 1-Boc-4-piperidone (2 g, 10.04 mmol), hydroxylamine hydrochloride (1.4 g, 20.08 mmol), and potassium acetate (1.97 g, 20.07 mmol) in EtOH (20 mL) was heated overnight at 90°C. After cooling to room temperature, the mixture was concentrated, and the residue was dissolved in water (20 mL). The aqueous layer was extracted with ELISA (3 × 20 mL). The combined organic layers were washed with saturated NaHCO3 (25 mL) aqueous solution and brine (25 mL), separated, dried over Na2SO4, filtered, and concentrated to obtain tert-butyl 4-hydroxyiminopiperidine-1-carboxylate (2.067 g, 9.64 mmol, yield 96%) as a white solid. UPLC-MS (ES+ , low acidity): 1.36 min, m / z 215.0 [M+H] + . 1 1H NMR (40 0MHz, DMSO-d6) δ / ppm: 10.44 (1H, s), 3.44-3.35 (4H, m), 2.46-2.41 (2H, m), 2.24-2.19 ( 2 hours (m), 1.40 (9 hours (s)).

[0352] Step 2: tert-butyl 3-amino-4,4-diethoxy-piperidine-1-carboxylate A mixture of tert-butyl 4-hydroxyiminopiperidine-1-carboxylate (2.06 g, 9.63 mmol), potassium carbonate (2.66 g, 19.28 mmol), and p-toluenesulfonyl chloride (1.84 g, 9.64 mmol) in THF (50 mL) was stirred at room temperature for 24 hours, and then heated at 40 °C for 20 hours. After cooling to room temperature, the mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in EtOH (20 mL) and added dropwise to a mixture of potassium ethoxide (1.62 g, 19.27 mmol) and anhydrous Na2SO4 (5.47 g, 38.54 mmol) in EtOH (20 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at room temperature for 1.5 hours, and then heated at 60 °C for 1 hour. After cooling to room temperature, the mixture was filtered and the filtered solid was washed with EtOH. The filtrate was concentrated, and the residue was purified by column chromatography using MeOH / DCM with a gradient of 0-8% as the eluent to obtain tert-butyl 3-amino-4,4-diethoxy-piperidine-1-carboxylate (1.181 g, 4.10 mmol, yield 43%) as a dark yellow oil. UPLC-MS (ES+, low acidity): 1.25 min, m / z 289.1 [M+H] + .

[0353] Step 3 tert-butyl4,4-diethoxy-3-[[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carbonyl]amino]piperidine-1-carboxylate A mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (585 mg, 1.72 mmol), tert-butyl 3-amino-4,4-diethoxypiperidine-1-carboxylate (741 mg, 2.57 mmol), propylphosphonic anhydride (2.05 mL, 3.44 mmol), and N,N-diisopropylethylamine (0.9 mL, 5.17 mmol) in THF (17.2 mL) was heated at 65°C for 2 hours. The mixture was concentrated, and the residue was dissolved in ELISA (100 mL). The organic layer was washed with water (2 × 30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain tert-butyl 4,4-diethoxy-3-[[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carbonyl]amino]piperidine-1-carboxylate (1049.7 mg, 1.72 mmol, yield 100%) as a pale orange foam. The compound was used directly in the next step without further purification. UPLC-MS (E S+, low acidity): 1.79 min, m / z 611.7 [M+H] + .

[0354] Step 4 tert-butyl2-[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate A mixture of tert-butyl 4,4-diethoxy-3-[[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carbonyl]amino]piperidine-1-carboxylate (1.05 g, 1.72 mmol), ammonium acetate (2.65 g, 34.38 mmol), and p-toluenesulfonic acid monohydrate (65.4 mg, 0.34 mmol) in 1-butanol (11.5 mL) was irradiated at 150 °C for 1.5 hours. Additional ammonium acetate (2.65 g, 34.38 mmol) and p-toluenesulfonic acid monohydrate (65.4 mg, 0.34 mmol) were added, and the mixture was further irradiated at 150 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in ELISA (100 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (30 mL), water (30 mL), and brine (30 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography using MeOH / DCM with a 0-10% gradient as the eluent to obtain tert-butyl2-[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizin-4-yl)oxy]chroman-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (214 mg, 0.41 mmol, yield 24%) as an off-white solid. UPLC-MS (ES+, low acidity): 1.27 min, m / z 518.4 [M+H] + .

[0355] Step 5: 5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one A mixture of tert-butyl 2-[6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (214 mg, 0.41 mmol) in DCM (2.5 mL) was mixed with TFA (0.5 mL, 6.53 mmol) and stirred in a sealed vial at 25°C for 1.5 hours. The mixture was concentrated, and the residue was azeotropically removed with toluene. The residue was dissolved in water and loaded onto an SCX-2 column. The column was washed with MeOH, then with NH3 (2N) in methanol, and the product was eluted. The filtrate was concentrated. The compound was dried to obtain 5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (84 mg, 0.20 mmol, yield 49%) as a yellow solid. The compound was used in the next step without further purification. UPLC-MS (ES+, low acidity): 0.97 min, m / z 418.1 [M+H] + .

[0356] Step 6: 5-[3-(5-isopropyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one A mixture of 5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (65 mg, 0.16 mmol), acetone (22.9 μL, 0.31 mmol), sodium triacetoxyborohydride (66.1 mg, 0.31 mmol), and acetic acid (17.9 μL, 0.31 mmol) in DMF (1.5 mL) was stirred at 25°C. After 23 and 30 hours, additional acetone (22.9 μL, 0.31 mmol) and sodium triacetoxyborohydride (66.1 mg, 0.31 mmol) were added, and the mixture was stirred for a further 48 hours at 25°C. The mixture was concentrated, and the residue was purified by reverse-phase column chromatography using (MeCN + 0.1% formic acid) / (H2O + 0.1% formic acid) as the eluent with a gradient of 0-40%. The fraction containing the product was dried and loaded onto an SCX-2 column, which was flushed first with MeOH and then with NH3(2N) in MeOH to elute 5-[3-(5-isopropyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (20.9 mg, 0.046 mmol, yield 29%) as a white solid. UPLC-MS (ES+, final purity) degrees): 2.05 minutes, m / z 460.2 [M+H] + . 1 1H NMR (400MHz, DMSO-d6+ 3 drops of CF3CO2D) δ / ppm: 8.03 ( 1H, d, J = 6.1Hz), 7.04 (1H, d, J = 2.7Hz), 6 .97 (1H, dd, J = 8.8Hz, 2.7Hz), 6.91 (1H, d, J = 8.8Hz), 6.36 (1H, d, J = 6.1Hz), 4.50-4. 44 (2H, m), 4.44-4.37 (2H, m), 3.92-3.84 (1 H, m), 3.83-3.68 (2H, m), 3.45-3.20 (3H, m) , 3.07-2.91 (4H, m), 2.61-2.55 (2H, m), 1.3 3 (6H, d, J = 6.6Hz). No exchangeable protons are observed.

[0357] Example 44. Synthesis of 5-[3-(5-acetyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (compound 135) [ka] Compound 135 was synthesized in the same manner as in Example 43, except for step 6 below: 5-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-yl) To a solution of chroman-6-yl)oxy-3,4-dihydro-1H-1,8-naphthyridine-2-one (36 mg, 0.09 mmol) and triethylamine (12 μL, 0.09 mmol) in DMF (0.8 mL), acetic anhydride (8.2 μL, 0.09 mmol) was added at 0°C, and the mixture was stirred at this temperature for 2 hours. The mixture was concentrated, and the residue was purified by column chromatography using (MeCN + 0.1% formic acid) / (H2O + 0.1% formic acid) as the eluent with a gradient of 0-40%. The fraction containing the product was concentrated and loaded onto an SCX-2 column, which was flushed first with MeOH and then with NH3(2N) in MeOH to obtain 5-[3-(5-acetyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyrizin-2-one (15.5 mg, 0.034 mmol, yield 39%) as a white solid. UPLC-MS (ES+, final purity): 2.22 and 2.25 min, m / z 460.2 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ / ppm: 12.08 (1H, br s), 10.45 (1H, s), 7.95 ( 1H, d, J = 5.8Hz), 6.97 (1H, d, J = 2.6Hz), 6 .90 (1H, dd, J = 8.8Hz, 2.6Hz), 6.86 (1H, d, J = 8.8Hz), 6.25 (1H, d, J = 5.8Hz), 4.46-4. 31 (3H, m), 4.11-4.01 (1H, m), 3.75-3.63 (2 H, m), 3.18-3.09 (1H, m), 3.09-3.00 (1H, m) , 2.95-2.89 (2H, m), 2.66-2.61 (1H, m), 2.5 6-2.51 (3H, m), 2.08 and 2.05 (3H, 2s, acetamide) (Isomer). 1H disappears (below the water / DMSO peak).

[0358] Example 45. Chiral separation of selected compounds As shown, the conditions disclosed in the table below can be used to separate stereoisomers of racemic compounds. [Table 26]

[0359] Example 46. Biological assay HCT-116 AlphaLISA SureFire pERK1 / 2 Cell Assay Human HCT-116 colorectal cancer cell line (ATCC CCL-247) is KRAS G13DThe mutation is endogenously expressed, leading to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. To determine whether the compound inhibits constitutive ERK phosphorylation in HCT-116 cells, the compound was tested using AlphaLISA® SureFire® technology (Perkin Elmer p-ERK1 / 2 p-T202 / Y204 assay kit ALSU-PERK-A10K). Assay readout was performed 2 or 24 hours after compound administration. On day 1, HCT-116 cells were harvested and fed growth medium (Glutamax (Life Technologies 36600021) and 10% heat-inactivated fetal bovine serum (Sigma F9)). The cells were resuspended in McCoys 5A containing 665) and counted. Cells were plated into each well of a 96-well culture dish (Sigma CLS3598) with 100 μl per well, up to a final cell density of 30,000 (2-hour read) or 15,000 (24-hour read) cells per well, and incubated overnight at 37°C and 5% CO2. On day 2, the growth medium was replaced with administration medium (McCoys 5A containing Glutamax (Life Technologies 36600021) and 1% thermo-inactivated fetal bovine serum (Sigma F9665)), and the compound was administered to the cells to produce a 10-point dose-response, with the peak concentration being 1 μM, and thereafter the concentration was measured at 1 / 3 logarithmic dilution intervals. A matched DMSO control was included. Cells were then incubated at 37°C and 5% CO2 for 2 or 24 hours. After incubation, the culture medium was removed, and the cells were incubated with a lysis buffer containing a phosphatase inhibitor at room temperature for 15 minutes. The cell lysates were transferred to a 1 / 2 area 96-well white Optiplate™ (Perkin Elmer 6005569) and incubated with anti-mouse IgG acceptor beads, a biotinylated anti-ERK1 / 2 rabbit antibody that recognizes both phosphorylated and unphosphorylated ERK1 / 2, a mouse antibody that targets the Thr202 / Tyr204 epitope and recognizes only phosphorylated ERK protein, and streptavidin-coated donor beads. The biotinylated antibody binds to the streptavidin-coated donor beads, and the phopsho-ERK1 / 2 antibody binds to the acceptor beads. The plate was read with an EnVision reader (Perkin Elmer). Laser excitation of the beads at 680 nm induced the release of singlet oxygen molecules from the donor beads, triggering energy transfer to the adjacent acceptor beads, producing a signal that could be measured at 570 nm. Both antibodies bound to phosphorylated ERK protein, bringing the donor and acceptor beads into close proximity. All data were analyzed using the Dotmatics or GraphPad Prism software package. Absolute IC 50 The inhibition of ERK phosphorylation was evaluated by determining the values. Absolute IC50 The value is defined as the concentration of the compound required to reduce the level of phosphorylated ERK protein by 50% compared to the DMSO control.

[0360] WiDr AlphaLISA SureFire pERK1 / 2 Cell Assay Human WiDr colorectal adenocarcinoma cell line (ATCC CCL-218) is BRAF V600E The mutation is endogenously expressed, leading to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. To determine whether the compound inhibits constitutive ERK phosphorylation in WiDr cells, the compound was tested using AlphaLISA® SureFire® technology (Perkin Elmer p-ERK1 / 2 p-T202 / Y204 assay kit ALSU-PERK-A10K). The main procedure was essentially the same as for HCT-116 cells (above), but the following adjustments were made to the growth medium (Eagle Minimal Essential Medium (Sigma M2279) containing 1× Glutamax (Life Technologies 35050038), 1× sodium pyruvate (Sigma S8636), and 10% thermo-inactivated fetal bovine serum (Sigma F9665)): administration medium (Eagle Minimal Essential Medium (Sigma M2279) containing 1× Glutamax (Life Technologies 35050038), 1× sodium pyruvate (Sigma S8636), and 1% thermo-inactivated fetal bovine serum (Sigma F9665)), and seeding density (2 hours: 50,000 cells per well; 24 hours: 35,000 cells per well). Furthermore, the compound was administered at a maximum concentration of 10 μM at 1 / 2 logarithmic dilution intervals.

[0361] HCT-116 AlphaLISA SureFire pERK1 / 2 cell assay (dimer) Human HCT-116 colorectal cancer cell line (ATCC CCL-247) is KRAS G13D The mutation is endogenously expressed, thereby constitutively activating the MAP kinase pathway and ERK This leads to phosphorylation. First-generation RAF inhibitors may promote RAF dimerization in KRAS-mutated tumors. This results in paradoxical activation of the pathway. To determine whether a compound can circumvent this problem and inhibit RAF dimerization in HCT-116 cells, the compound was tested using AlphaLISA® SureFire® technology (PerkinElmer p-ERK1 / 2 p-T202 / Y204 assay kit ALSU-PERK-A10K). The main procedure was essentially the same as above, with the following adjustments: Cells were seeded at a seeding density of 30,000 cells per well. On day 2 (administration day), without changing the medium, cells were administered 1 μM encorafenib for 1 hour (at 37°C and 5% CO2) to induce RAF dimerization and promote paradoxical dimer-dependent pERK signaling. After incubation, the cells were washed, 100 μl of fresh growth medium was added, and the target compound was administered to the cells to induce a 10-point dose-response, with the peak concentration being 10 μM. Subsequent concentrations were measured at 1 / 2 logarithmic dilution intervals. Prior to lysis and treatment with the pERK AlphaLISA® SureFire® kit as described above, the cells were further incubated at 37°C and 5% CO2 for 1 hour.

[0362] A375 AlphaLISA SureFire pERK1 / 2 Cell Assay (Monomer) Human A375 melanoma cell line (ATCC CRL-1619) is BRAF V600E The mutation is endogenously expressed, leading to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. BRAF V600EIn mutant tumors, BRAF signals as a monomer that activates ERK. To determine whether a compound can inhibit the BRAF monomer in A375 cells, the compound was tested using AlphaLISA® SureFire® technology (PerkinElmer p-ERK1 / 2 p-T202 / Y204 assay kit ALSU-PERK-A10K). The main procedure for HCT-116 cells was essentially the same as above, but with the following adjustments: A375 cells were cultured and administered to Dulbecco's Modified Eagle Medium containing 4.5 g / L D-glucose (Sigma D6546), 10% thermoinactivated fetal bovine serum (Sigma F9665), and 1% sodium pyruvate (Sigma S8636), and seeded at a seeding density of 30,000 cells per well. Without changing the culture medium before administering the compound, a 10-point dose-response was observed, with the peak concentration being 10 μM and subsequent concentrations at 1 / 2 logarithmic dilution intervals. Subsequently, the cells were incubated at 37°C and 5% CO2 for 1 hour before lysis.

[0363] HCT-116 CellTiter-Glo 3D Cell Proliferation Assay Human HCT-116 colorectal cancer cell line (ATCC CCL-247) is KRAS G13D The mutation is endogenously expressed, resulting in enhanced survival and proliferation signaling. To determine whether the compound inhibits the proliferation of HCT-116 cells, the CellTiter-Glo® 3D cell viability assay kit (Promega) was used. The compound was tested using G9683). On day one, HCT-116 cells were harvested and resuspended in growth medium (McCoys 5A containing Glutamax (Life Technologies 36600021) containing 10% heat-inactivated fetal bovine serum (Sigma F9665)) and counted. Cells were plated in each well of a Corning 7007 96-well clear round-bottom ultra-low adhesion plate (VWR 444-1020) in 100 μl per well, up to a final density of 1000 cells per well. Cells were seeded for pre-treatment and post-treatment readings. The cells were then incubated at 37°C and 5% CO2 for 3 days (72 hours) to form spheroids. After 72 hours, the plate seeded for pre-treatment readings was removed from the incubator and allowed to equilibrate at room temperature for 30 minutes before adding CellTitle-Glo® reagent to each well. Incubate the plate at room temperature for 5 minutes while shaking at 300 rpm, then proceed as follows: The cells were incubated on a benchtop for 25 minutes before being read with an Envision reader (Perkin Elmer). On the same day, the compound was administered to the cells plated for post-treatment readout to produce 9 dose-response points, with the highest concentration being 15 μM and the lowest concentrations being at 1 / 2 logarithmic dilution intervals. These cells were then incubated for a further 4 days (96 hours) at 37°C and 5% CO2. After 4 days, the plates were removed from the incubator, equilibrated at room temperature for 30 minutes, and treated with CellTitre Glo® reagent as described above. The method allows for the quantification of ATP present in the wells, which is directly proportional to the amount of viable—and therefore metabolically active—cells in 3D cell culture. CellTitre Glo® reagent lyses cells and contains luciferin and luciferase (Ultra-Glo® recombinant luciferase), which can produce bioluminescence from luciferin in the presence of ATP and oxygen. Therefore, plates were read with an EnVision reader (Perkin Elmer) and the luminescence signal was recorded. Cell proliferation was determined on day 4 post-treatment by comparing it with pre-treatment readings. All data were analyzed using the Dotmatics or GraphPad Prism software package. The GI was defined as the concentration of the compound required to reduce the level of cell proliferation by 50% compared to the DMSO control. 50 The inhibition of proliferation was evaluated by determining the values.

[0364] WiDrCellTiter-Glo 3D Cell Proliferation Assay Human WiDr colorectal adenocarcinoma cell line (ATCC CCL-218) is BRAF V600EThe mutation is endogenously expressed, resulting in enhanced signaling for survival and proliferation. To determine whether the compound inhibits the proliferation of WiDr cells, the compound was tested using the CellTiter-Glo® 3D cell viability assay kit (Promega G9683) as described for HCT-116 cells, with the following adjustments made to the growth medium: Eagle's Minimum Essential Medium (Sigma M2279) containing 1× Glutamax (Life Technologies 35050038), 1× sodium pyruvate (Sigma S8636), and 10% thermo-inactivated fetal bovine serum (Sigma F9665).

[0365] Microsome Stability Assay Stability studies were manually performed using a substrate depletion approach. The test compound was subjected to a protein concentration of 0.5 mg / mL. -1 The final substrate concentration was 1 μM and incubated with cryopreserved mouse or human liver microsomes (Corning) at 37°C. Aliquots were removed from the incubation at predetermined time points, and the reaction was terminated by adding ice-cold organic solvent. Compound concentrations were determined by LC-MS / MS analysis. The natural logarithm of the percentage of remaining compound was plotted against each time point, and the slope was determined. The half-lives (t) were calculated using equations 1 and 2, respectively. 1 / 2 ) and CL int The following was calculated. Data analysis was performed using Excel (Microsoft, USA).

[0366] t 1 / 2 (Minimum) = 0.693 / -Slope (1)

[0367] CL int (μL / min / mg) = (LN(2) / t 1 / 2 (min) * 1000 / microsomal protein (mg / mL) (2)

[0368] The results of the HLM (human liver microsome) and MLM (mouse liver microsome) stability assays are shown in Tables 1 and 2.

[0369] Plasma protein binding assay Plasma protein binding was determined by equilibrium dialysis. Using the RED device (Life Technologies), pre-frozen human or mouse plasma (Sera La) was analyzed. A compound (5 μM) at a known concentration in bs) was dialyzed in phosphate buffer at 37°C for 4 hours. The concentrations of the compound on the protein-containing (PC) and protein-free (PF) sides of the dialysis membrane were determined by LC-MS / MS, and the % free compound was determined using Equation 4. Data analysis was performed using Excel (Microsoft, USA).

[0370] % free = (1 - ((PC - PF) / PC)) × 100 (4)

[0371] The results for hPPB (human plasma protein binding) and mPPB (mouse plasma protein binding) are shown in Tables 1 and 2.

[0372] FeSSIF solubility assay 1 mL of ingested intestinal fluid (FeSSIF), prepared using FaSSIF / FeSSIF / FaSSGF powder (Biorelevant.com) and pH 5 acetate buffer, was added to 1.0 mg of the compound and incubated for 24 hours (Bioshake iQ, 650 rpm, 37°C). After filtration under positive pressure, the concentration of the compound in the solution was evaluated by LC-UV compared to the response of a calibration standard of known concentration (250 μM). The solubility results of FeSSIF are shown in Tables 1-2.

[0373] [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4]

[0374] [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4] [Table 28-5]

[0375] The publications discussed herein are provided solely for disclosure prior to the filing date of this application. This specification should not be construed as acknowledging that...

Claims

1. Compounds of formula (I), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: 【Chemistry 1】 (In the formula, Ring A is a five-membered heterocyclic ring or heteroaryl ring containing one, two, or three nitrogen atoms as ring members. R １ or R ２ One of them is substitution C １－８ Alkyl, unsubstituted C ５－８ Alkyl, substituted, or unsubstituted C １－８ A haloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted heteroaryl, and the other R １ or R ２ Is it H? Alternatively, R １ and R ２ together with the atoms to which they are attached form a 5- or 6-membered saturated, partially unsaturated or unsaturated ring containing 0, 1 or 2 heteroatoms selected from N, O or S, wherein said ring is substituted or unsubstituted, If ring A is an imidazole, the substituted aryl is 【Chemistry 2】 Instead, If ring A is an imidazole, then R １ and R ２ (These atoms, along with the atoms to which they are bonded, do not form an unsubstituted phenyl ring.)

2. The compound according to claim 1, wherein ring A is imidazole, pyrazole, or triazole.

3. Ring A is 【Transformation 3】 The compound according to claim 1 or 2.

4. The compound according to claim 1 having the structure of formula (I-A), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer: 【Chemistry 4】 (In the formula, R １ or R ２ One of them is substitution or non-substitution C ５－８ Alkyl, substituted, or unsubstituted C １－８ A haloalkyl, substituted aryl, substituted or unsubstituted heterocyclyl, or substituted heteroaryl, and the other R １ or R ２ Is it H? Alternatively, R １ and R ２ However, together with the atoms to which they are bonded, they form a 5-membered or 6-membered saturated ring, a partially unsaturated ring, or an unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the ring is substituted or unsubstituted. The aforementioned substitution aryl is 【Transformation 5】 Instead, R １ and R ２ (These atoms, along with the atoms to which they are bonded, do not form unsubstituted phenyl compounds.)

5. One or more substituents are halogens, -OR Ａ , -NR Ａ R Ｂ , -SO ２ R Ｃ , -SOR Ｃ ,-CN,C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, or -C(O)C １－６ Selected from alkyl groups, R Ａ and R Ｂ However, H and C are independent of each other. １－６ Alkyl, or C １－６ It is a haloalkyl, R Ｃ However, C １－６ Alkyl or C １－６ It is a haloalkyl, The alkyl group, haloalkyl group, and cycloalkyl group can independently be -OR Ａ -CN, -SOR Ｃ , -NR Ａ R Ｂ , or -NR Ｄ R Ｅ It is arbitrarily substituted with 1 to 3 groups selected from the following: R Ｄ and R Ｅ However, together with the N atom to which they are bonded, they form a 5-membered or 6-membered saturated or partially unsaturated ring containing one or two heteroatoms selected from N, O, or S, and the saturated or partially unsaturated ring is C １－６ Optionally substituted with alkyl groups, The compound according to any one of claims 1 to 4.

6. R １ and R ２ The compound according to any one of claims 1 to 5, wherein, together with the atoms to which they are bonded, they form a five-membered or six-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, and the ring is substituted or unsubstituted.

7. R １ and R ２ The compound according to claim 6, wherein together with the atoms to which they are bonded, they form a six-membered partially unsaturated or unsaturated ring containing zero or one nitrogen atom in the ring, and the ring is substituted or unsubstituted.

8. R １ and R ２ The compound according to claim 6 or 7, wherein, together with the atoms to which they are bonded, they form a substituted or unsubstituted phenyl ring or a substituted or unsubstituted pyridyl ring.

9. R １ and R ２ The compound according to claim 6 or 7, wherein they form a substituted or unsubstituted tetrahydropyridyl ring together with the atoms to which they are bonded.

10. The compound according to claim 1, wherein the compound has the structure of formula (I-B), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer: 【Transformation 6】 (In the formula, R １ or R ２ One of them is a substituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted heteroaryl. The aforementioned substitution aryl is 【Transformation 7】 isn't it).

11. R １ The compound according to any one of claims 1 to 10, wherein the compound is a substituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted heteroaryl.

12. R １ The compound according to any one of claims 1 to 11, wherein the compound is a substituted phenyl or a substituted five-membered or six-membered N-heteroaryl.

13. R １ The compound according to any one of claims 1 to 12, wherein the compound is a substituted phenyl, a substituted pyridyl, a substituted pyrazole, a substituted pyrimidinyl, or a substituted thiophenyl.

14. R １ The compound according to claim 11, wherein the compound is a monocyclic or bicyclic substituted aryl, or a monocyclic or bicyclic substituted heteroaryl.

15. R １ The compound according to claim 1, wherein the compound is a monocyclic or bicyclic substituted or unsubstituted aryl compound.

16. The compound according to claim 14 or 15, wherein the bicyclic aryl or bicyclic heteroaryl is a condensed bicyclic aryl or a condensed bicyclic heteroaryl.

17. R １ The compound according to claim 11, wherein the compound is a substituted indazole or a substituted benzimidazole.

18. R １ The compound according to any one of claims 1 to 10, wherein the compound is an unsubstituted or substituted heterocycline containing 0, 1, or 2 heteroatoms selected from N, O, or S.

19. R １ The compound according to any one of claims 1 to 10, wherein the compound is a substituted or unsubstituted tetrahydropyran.

20. R １ However, substitution or non-substitution C ５－６ The compound according to any one of claims 1 to 10, wherein it is alkyl.

21. R １ The compound according to any one of claims 1 to 10, wherein the compound is substituted with one or two substituents.

22. The substituents are halogen, -OR Ａ , -NR Ａ R Ｂ , -SO ２ R Ｃ , -SOR Ｃ ,-CN,C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, or -C(O)C １－６ Selected from alkyl groups, R Ａ and R Ｂ However, H and C are independent of each other. １－６ Alkyl, or C １－６ It is a haloalkyl, R Ｃ However, C １－６ Alkyl or C １－６ It is a haloalkyl, The alkyl group, haloalkyl group, and cycloalkyl group are independently -OR Ａ -CN, -SOR Ｃ , or -NR Ａ R Ｂ It is arbitrarily replaced by one to three groups selected from the following: The compound according to any one of claims 1 to 21.

23. Said substituent is halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -C(O)CH ３ , -CN, -OH, -NH ２ , -NH(C １－３ alkyl), -N(C １－３ Alkyl) ２ ien-CH ２ NH ２ ien-CH ２ NH(C) １－３ Alkyl), or -CH ２ N(C) １－３ Alkyl) ２ A compound according to any one of claims 1 to 22, selected from the above.

24. The substituents on the substituted aryl or substituted heteroaryl are methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, and -CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CH ２ F, -CH ２ CHF ２ ien-CH ２ CF ３ , -C(O)CH ３ , -CN, -OH, -NH ２ ,-NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ ien-CH ２ NH ２ ien-CH ２ NH(C) １－３ Alkyl), or -CH ２ N(C) １－３ Alkyl) ２ A compound according to any one of claims 1 to 23, selected from the above.

25. The compound according to any one of claims 1 to 24, wherein the compound has (R) or (S) stereochemistry at the carbon indicated by *.

26. The compound according to claim 1, wherein the compound is selected from Table A-1, Table A-2, or Table A-3, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

27. Compounds of formula (II), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: 【Transformation 8】 (In the formula, X １ and X ２ These are N or CH, respectively. R １ is substitution C １－８ Alkyl, unsubstituted C ５－８ Alkyl, substituted, or unsubstituted C １－８ A haloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted heteroaryl, R ４ -NR Ｆ C(O)R ５ , -NR Ｆ C(O)CH ２ R ５ , -NR Ｆ C(O)CH(CH ３ ) R ５ , or -NR Ｆ R ５ And, R ５ is a substituted or non-substituted element selected from alkyl, carbocyryl, aryl, heterocyclyl, or heteroaryl. R Ｆ is H or C １－３ (It is alkyl.)

28. X １ and X ２ The compound according to claim 27, wherein one of the elements is N.

29. X １ and X ２ The compound according to claim 27, wherein both are CH.

30. R １ The compound according to any one of claims 27 to 29, wherein the compound is a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted heteroaryl.

31. R １ However, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or non The compound according to any one of claims 27 to 30, which is a substituted pyrazole, a substituted or unsubstituted pyrimidinyl, or a substituted or unsubstituted thiophenyl.

32. R ４ However, -NHC(O)R ５ , -NHC(O)CH ２ R ５ , -NHC(O)CH(CH ３ ) R ５ , or -NHR ５ The compound according to any one of claims 27 to 31.

33. R ５ The compound according to any one of claims 27 to 32, wherein the substituent or non-substituent is selected from alkyl, 3-6 membered carbocyryl, phenyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl.

34. R ５ The compound according to any one of claims 27 to 33, wherein the compound is a substituted or unsubstituted compound selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrazole, or triazole.

35. R Ｆ The compound according to any one of claims 27 to 34, wherein the compound is H or methyl.

36. The substituents are halogen, -OR Ａ , -NR Ａ R Ｂ , -SO ２ R Ｃ , -SOR Ｃ ,-CN,C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, or -C(O)C １－６ Selected from alkyl groups, R Ａ and R Ｂ However, H and C are independent of each other. １－６ Alkyl, or C １－６ It is a haloalkyl, R Ｃ However, C １－６ Alkyl or C １－６ It is a haloalkyl group; the alkyl group, haloalkyl group, and cycloalkyl group are independently -OR Ａ -CN, -SOR Ｃ , or -NR Ａ R Ｂ It is arbitrarily replaced by one to three groups selected from the following: The compound according to any one of claims 27 to 35.

37. The substituents include halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, and -CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CH ２ F, -CH ２ CHF ２ ien-CH ２ CF ３ , -C(O)CH ３ , -CN, -OH, -NH ２ ,-NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ ien-CH ２ NH ２ ien-CH ２ NH(C) １－３ Alkyl), or -CH ２ N(C) １－３ Alkyl) ２ A compound according to any one of claims 27 to 35, selected from the above.

38. R ５ However, halogen, methyl, ethyl, propyl, isopropyl, -CN, -OH, or -NH ２ The compound according to any one of claims 27 to 37, which is substituted with one or more substituents selected from the following.

39. The compound according to any one of claims 27 to 38, wherein the compound has (R) or (S) stereochemistry at the carbon indicated by *.

40. The compound according to claim 27, wherein the compound is selected from Table B, or from pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

41. Compounds of formula (III), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: 【Chemistry 9】 (In the formula, R ６ is -C(O)NR Ｆ R ５ , -C(O)NR Ｆ CH ２ R ５ , substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, R ５ is a substitution or non-substituent selected from carbocyclyl, aryl, heterocyclyl, or heteroaryl, R Ｆ is H or C １－３ (It is alkyl.)

42. R ６ However, -C(O)NHR ５ or -C(O)NHCH ２ R ５ The compound according to claim 41.

43. R ５ The compound according to claim 41 or 42, wherein the compound is a substituted or unsubstituted aryl.

44. R ６ The compound according to claim 41, wherein the compound is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

45. R ６ The compound according to claim 44, wherein the compound is a monocyclic or bicyclic substituted aryl, or a monocyclic or bicyclic substituted heteroaryl.

46. The compound according to claim 45, wherein the bicyclic aryl or bicyclic heteroaryl is a condensed bicyclic aryl or a condensed bicyclic heteroaryl.

47. R ６ The compound according to any one of claims 44 to 46, wherein the compound is a substituted or unsubstituted indazole, or a substituted or unsubstituted benzimidazole.

48. The substituents are halogen, -OR Ａ , -NR Ａ R Ｂ , -SO ２ R Ｃ , -SOR Ｃ ,-CN,C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, or -C(O)C １－６ Selected from alkyl groups, R Ａ and R Ｂ However, H and C are independent of each other. １－６ Alkyl, or C １－６ It is a haloalkyl, R Ｃ However, C １－６ Alkyl or C １－６ It is a haloalkyl group; the alkyl group, haloalkyl group, and cycloalkyl group are independently -OR Ａ -CN, -SOR Ｃ , or -NR Ａ R Ｂ It is arbitrarily replaced by one to three groups selected from the following: The compound according to any one of claims 41 to 47.

49. The substituents include halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, and -CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CH ２ F, -CH ２ CHF ２ ien-CH ２ CF ３ , -C(O)CH ３ , -CN, -OH, -NH ２ ,-NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ ien-CH ２ NH ２ ien-CH ２ NH(C) １－３ Alkyl), or -CH ２ N(C) １－３ Alkyl) ２ A compound according to any one of claims 41 to 47, selected from the above.

50. R ６ However, it is a substituted aryl, substituted heterocyclyl, or substituted heteroaryl. The substituents include halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, and -CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CH ２ F, -CH ２ CHF ２ ien-CH ２ CF ３ , -C(O)CH ３ , -CN, -OH, -NH ２ ,-NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ ien-CH ２ NH ２ ien-CH ２ NH(C) １－３ Alkyl), -CH ２ N(C) １－３ Alkyl) ２ , selected from optionally substituted phenyl or optionally substituted heteroaryl, The compound according to any one of claims 41 to 49.

51. R ６ However, it is a substituted aryl or substituted heteroaryl, and the substituent is one or two C １－３ The compound according to any one of claims 41 to 50, which is a phenyl or pyrazole substituted with an alkyl group.

52. The compound according to claim 41, selected from Table C, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

53. structure 【Chemistry 10】 Compounds having, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

54. A pharmaceutical composition comprising a compound according to any one of claims 1 to 53 and a pharmaceutically acceptable excipient or carrier.

55. Furthermore, the pharmaceutical composition according to claim 54, comprising an additional therapeutic agent.

56. The pharmaceutical composition according to claim 55, wherein the additional therapeutic agent is an antiproliferative agent or antitumor agent, a cell proliferation inhibitor, an anti-invasion agent, a growth factor function inhibitor, an anti-angiogenic agent, a steroid, a targeted therapy agent, or an immunotherapy agent.

57. A method for treating a condition regulated by RAF kinase, comprising administering an effective amount of the compound described in any one of claims 1 to 53 to a subject in need thereof.

58. The method according to claim 57, wherein the condition can be treated by inhibiting one or more Raf kinases.

59. The aforementioned condition is cancer, sarcoma, melanoma, skin cancer, hematological malignancy, lymphoma, carcinoma, or leukemia The method according to claim 57 or 58.

60. The aforementioned conditions include: Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; bile duct cancer; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastases to the central nervous system from tumors originating outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancer; head and neck squamous cell carcinoma; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; The method according to claim 57 or 58, selected from non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; metastatic melanoma; or thyroid cancer.

61. A method for treating cancer, comprising administering an effective amount of a compound according to any one of claims 1 to 53 to a subject in need thereof.

62. The method according to claim 61, wherein the cancer comprises at least one mutation in the BRAF kinase.

63. The aforementioned cancer is BRAF Ｖ６００Ｅ The method according to claim 62, including a mutation.

64. The method according to claim 62, wherein the cancer is selected from melanoma, thyroid cancer, Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastoma, astrocytoma, ependymoma, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, hematological cancer, leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, kidney cancer, sarcoma, uveal melanoma, or skin cancer.

65. The aforementioned cancer is BRAF Ｖ６００Ｅ Melanoma, BRAF Ｖ６００Ｅ Colorectal cancer, BRAF Ｖ６００Ｅ Papillary thyroid cancer, BRAF Ｖ６００Ｅ Low-grade serous ovarian cancer, BRAF Ｖ６００Ｅ Glioma, BRAF Ｖ６００Ｅ Hepatobiliary cancer, BRAF Ｖ６００Ｅ hairy cell leukemia, BRAF Ｖ６００Ｅ Non-small cell lung cancer, or BRAF Ｖ６００Ｅ The method according to claim 63, wherein the tumor is a pilocytic astrocytoma.

66. The method according to any one of claims 61 to 65, wherein the cancer is colorectal cancer.

Images